Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies Abstract Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD. As these drugs simply delay the onset of symptoms, the development of new therapies is key. As neurons are highly energy-demanding cells, they rely heavily on the functions of mitochondria, and any dysfunction affecting respiratory processes can be devastating and lead to the neuronal death characteristic of AD. Dysfunction in fission and fusion processes of mitochondria have been observed in early AD and are heavily involved in AD pathogenesis. Beta-amyloid (Aβ) is a neurotoxic protein formed in the AD brain as a result of inappropriate secretase activity and is one of the major hallmarks of the disease. Aβ has recently been discovered in the membranes of mitochondria, disabling many basic respiratory functions. Ongoing research is largely targeted at protecting mitochondria from damage caused by factors such as Aβ and oxidative stress. Antioxidants have been meticulously studied, and several generic antioxidants such as α-tocopherol have been found to significantly slow the rate of cognitive decline in both mild to moderate and severe AD. MitoQ is a mitochondria specific antioxidant which is able to enter mitochondria in an almost thousand fold greater concentration than is achieved by generic antioxidants. This enables protection against potentially devastating factors for mitochondria, such as lipid peroxidation, oxidative stress and Aβ neurotoxicity. This review further discusses mitochondrial therapies as well as other new treatments for AD. β-amyloid, acetylcholine, mitochondria, MitoQ, antioxidants, reactive oxygen species (ROS) Introduction Alzheimer's disease (AD) is the leading cause of dementia worldwide. Dementia patients totalled 24.2 million in 2005 and 4.2 million cases arose each year from 2005 to 2011, with 70% of these cases being a result of AD (Christiane, Brayne and Mayeux, 2011). AD predominantly affects more women than men, and the number of people dying as a result of the disease increased by 55.7 people per hundred thousand in the USA from 2000 to 2010 (Centers for Disease Control and Prevention, NCHS, 2008). Frequently, the cause of death of AD sufferers is a secondary condition such as pneumonia or ischaemic heart disease which can be exacerbated by many of the symptoms of AD (Brunnstrom and Englund, 2009). The number of people developing AD is expected to triple by the year 2050 (Mohammadi-Khanaposhtani et al., 2015), when it is estimated that 4.1% of the population will be over 80 years of age (Department of Economic and Social Affairs, 2001). In developed countries, 1 in 10 people over the age of 65 are affected by dementia of some form, with the frequency of AD almost doubling within this specific population every 5 years (Qiu, Kivipelto and von Strauss, 2009). Worldwide, the cost of medical care for dementia sufferers totals approximately 604 billion US$ (Fargo et al., 2014), with the annual cost of AD per patient ranging from between US$42 000 and US$56 000 in the USA (Hurd et al., 2013). Clearly AD is both widespread and costly. AD is a progressive, age-associated neurodegenerative disease which is characterized by neuronal loss and accompanying cognitive impairment (Walsh and Selkoe, 2007; Bonda et al., 2010), with symptoms ranging from ‘preclinical’ (Sperling et al., 2011) to severe. Early symptoms of AD may first be mistaken by friends and family members as normal signs of ageing, however as the disease progresses symptoms worsen rapidly, though the rate at which this happens differs between individuals. Later stages of the disease result in the sufferer being unable to perform everyday tasks such as carrying out basic hygiene routines, or being able to bathe or eat independently (Leifer, 2009). AD commonly goes undiagnosed until it reaches these more debilitating stages. The mini mental state examination is used to assess the level of cognitive impairment that a dementia patient may be experiencing via a series of exercises, such as memorizing a list of objects or correctly answering time-orientation questions (NHS-UK, 2015). Further tests such as blood tests and MRI or CT scans may then be taken, characteristically showing diminished brain tissue as a result of neuronal loss, forming a definitive diagnosis (Cullen et al., 2007). The most popular theory regarding AD onset is the role of Aβ, a fundamental component of extracellular plaques that accumulate in the brains of AD sufferers via amyloidogenesis (Picone et al., 2014). This process is known to be a leading cause of the neuronal loss that can be observed in AD and is a recognized hallmark of the disease (Bonda et al., 2010; Das, Murray and Belfort, 2015). Similarly, microtubule associated tau proteins become hyperphosphorylated and form neurofibrillary tangles which is also recognized as a hallmark of the disease (Bonda et al., 2010; Annamalai et al., 2015). It is thought that as well as these known hallmarks, mitochondrial malfunctions play a distinct role in AD pathogenesis (Obulesu and Lakshmi, 2014). The processes of fission and fusion are vital in mitochondrial dynamics in order to maintain a balance of the morphology, number, distribution, and function of these organelles within cells (Wang et al., 2009). When these processes become unbalanced, mitochondria are unable to adequately carry out their functions making them vulnerable to consequences such as oxidative stress which can lead to the neurodegeneration typically seen in AD (Bonda et al., 2010). This review will outline the pathophysiology of AD and the current medications used, and primarily focus on newer treatment strategies such as therapies targeted at mitochondrial dysfunction in neurons. It will explain the possible benefits of these newer treatment techniques, currently undergoing clinical testing, and demonstrate the difficulties associated with finding successful AD therapies. Pathophysiology of AD and currently available medications Pathophysiology of AD Amyloid precursor protein (APP) is a type I transmembrane protein which is synthesized in the endoplasmic reticulum (O'Brien and Wong, 2011) and found in the neuronal cell membrane, with a large extracellular N-terminus and a shorter intracellular C-terminus. APP must be cleaved into smaller fragments by proteases in order to be functional. In healthy brains, a protease known as α-secretase carries out the first cleavage followed by a secondary cleavage from γ-secretase, giving rise to the nonamyloidgenic pathway. This forms the alpha C-terminal fragment and also causes APP to release its extracellular domain, known as APPsα (Obregon et al., 2012), which are thought to be beneficial to neurons (Zhang et al., 2011). In AD, APP is formed incorrectly due to an excess of β-secretase. When APP is first cleaved by β-secretase as opposed to α-secretase, C-terminal fragment β-CTF along with the soluble N-terminal fragment APPsβ are generated. γ-secretase further processes the β-CTF fragment, forming Aβ fragments of varying lengths; Aβ40 and Aβ42 being the primary toxic species found in AD brains (Obregon et al., 2012). This is known as the amyloidgenic pathway (Obregon et al., 2012; Picone et al., 2014) (Fig. 1). As more Aβ40 and Aβ42 are released, the Aβ oligomers increase in size and become insoluble and increasingly toxic to neurons, forming the aforementioned Aβ plaques (Hayden and Teplow, 2013). Figure 1. Open in new tabDownload slide Nonamyloidgenic and amyloidgenic pathways originate from different APP processing. The nonamyloidgenic pathway sees cleavage of α-secretase produce the healthy APPsα fragment, with further cleavage of γ-secretase giving rise to no Aβ generation. In AD, β-secretase forms the initial cleavage producing the APPsβ fragment, with γ-secretase combining to produce Aβ plaques in the amyloidgenic pathway. (Reproduced from Menting and Claassen 2014, open access under the Creative Commons Attribution License CC-BY.) In the brains of healthy individuals, tau stabilizes components critical to the internal transport system of neurons. Tau attaches to microtubules along the length of the neuron, allowing nutrients and other metabolic substances to be transported throughout the cell (Guzman-Martinez, Farias and Maccioni, 2013). In AD brains, tau is modified, causing it to separate from the microtubules therefore resulting in their degradation. Intracellular tangles formed by tau protein hyperphosphorylation disable the transport system and inactivate the neuron. Neurons are unable to regenerate, therefore as these processes continue neurons begin to disconnect from each other and eventually die, leading to memory loss, cognitive decline and other symptoms associated with AD as the brain tissue gradually shrinks and loses function. In AD patients, cholinergic pathways become compromised in the basal forebrain and cerebral cortex (Herholz, 2008), primarily due to an excess amount of acetylcholinesterase (AChE), leading to a decrease in acetylcholine (ACh) levels (Zhou et al., 2015). These cholinergic deficits are thought by many to be a major factor in AD (Herholz, 2008; Biswas et al., 2015; Zhou et al., 2015). Evidence suggests that AChE can also interact with Aβ and increase the number and toxicity of Aβ plaques via interaction with AChEs peripheral binding site (Mantoani et al., 2016). Currently available medications to target neurotransmitters ACh has been found to be greatly reduced in sufferers of AD compared to healthy controls (Ankarcrona, Mangialasche and Winblad, 2010; Zhou et al., 2015). Drugs currently available on the UK National Health Service work primarily by reducing AChE levels and therefore restoring levels of cholinergic transmission in the brain. Drugs can also be prescribed which target glutamatergic transmission, as both glutamatergic and cholinergic transmission are impaired in the brains of AD sufferers (Cacabelos, 2007). There are four main drugs currently in use for the relief of symptoms of AD: donepezil, rivastigmine, galantamine and, usually only prescribed for severe AD, memantine. Donepezil is the most commonly prescribed drug for AD in more than 50 countries. It is a highly selective AChE inhibitor (AChEI) with a response rate of 40–58%, improving behaviour, cognition and quality of life in both moderate and severe AD (Sadowsky et al., 2014). Rivastigmine is another commonly prescribed AChEI. It is often a treatment of preference as it also inhibits butylcholinesterase, increased in those with AD and causing an imbalance with decreased levels of AChE (Mushtag et al., 2014), and it can be administered both orally and via transdermal patch (Cacabelos, 2007; Sasaki and Horie, 2014; Farlow et al., 2015), which can be beneficial for some patients if they display more violent and restless symptoms. Galantamine is a newer drug, and is an established AChEI which is also an allosteric modulator affecting nicotinic ACh receptors, alleviating both behavioural and psychiatric symptoms of mild to moderate AD (Cacabelos, 2007; Farokhnia et al., 2014). These three drugs are medications predominantly prescribed for mild to moderate AD, effective by restoring cholinergic pathways and delaying symptom progression. The majority of drug therapies for AD focus on treating mild to moderate AD symptoms, with only a minority being targeted at severe AD. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist (Zhu et al., 2013), is the leading drug in the treatment for severe AD along with donepezil and often the two are used in conjunction (Wenk, Parsons and Danysz, 2006). Memantine works primarily by blocking excess levels of glutamate, therefore preventing glutamatergic toxicity which can be fatal for neurons in AD brains. This is achieved without affecting normal glutamatergic transmission (Wenk, Parsons and Danysz, 2006). Memantine, though not as widely used as AChEIs, does show potential neuroprotective properties such as decreasing tau protein hyperphosphorylation and consequentially inhibiting neurofibrillary tangle formation and Aβ deposition, as well as reducing the amount of damage caused to neural cells by aiding the reduction of abnormal synaptic signals (Cacabelos, 2007). Role of mitochondria in disease pathogenesis Mitochondrial dynamics in neuronal cells: Fission, fusion and function Mitochondria are constantly dividing and fusing within cells depending on environmental demands (Chan, 2006). Neurons are highly demanding cells with regards to mitochondria and require large amounts of energy. Mitochondria provide the majority of their energy to the cell through oxidative phosphorylation during the TCA cycle (Knott and Bossy-Wetzel, 2008; Bonda et al., 2010), and provide energy for many ATP-dependent neuronal processes such as synaptic transmission, vesicle release, ion channel and receptor-related processes and the reuptake and recycling of neurotransmitters (Knott and Bossy-Wetzel, 2008). Fission and fusion are the two main processes by which the mitochondria remain in synchronization with the energy demands of cells (Fig. 2). These processes also allow the spread of mitochondrial DNA (mtDNA) and metabolites during fusion processes (Santos et al., 2010), and keep the amount of defective mitochondria in the cell at a low level during fission (Bonda et al., 2010). Both processes are largely mediated by guanosine triphosphatase (GTPase) enzymes. Fission, the process of two mitochondria arising from one mitochondrial division, largely relies on two proteins: the GTPase dynamin like protein 1 (DLP-1, or DNM1L), a cytosolic protein believed to be recruited to the outer mitochondrial membrane when required; and the small protein Fis1 (Bonda et al., 2010; Santos et al., 2010). Fis1 is an outer membrane protein, and is believed to be a DLP-1 receptor and involved in DLP-1 recruitment; however, the exact mechanism is still unknown (Knott and Bossy-Wetzel, 2008; Santos et al., 2010). Fusion of mitochondria is regulated by the large GTPases mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optic atrophy protein 1 (OPA1) (Bonda et al., 2010; Santos et al., 2010). Mfn1 and Mfn2 are transmembrane proteins which span the outer mitochondrial membrane and are involved in connecting the outer membranes of nearby mitochondria to each other. However, the inner membrane must also fuse to allow the intracellular contents to merge together, which is where OPA1 is involved (Santos et al., 2010). OPA1 is an inner membrane protein which faces the intermembrane space, and requires Mfn1, but not necessarily Mfn2, to mediate the process of inner mitochondrial membrane (IMM) fusion (Santos et al., 2010). Figure 2. Open in new tabDownload slide Schematic representation of mitochondrial fission and fusion events, regulated by the proteins: Mfn 1 and 2, Opa1, Dnm1L and Fis1. (Adapted with permission from the Company of Biologists Ltd., Mandemakers, Morais and De Strooper 2007). As well as the quantity of mitochondria in a cell at any one time, the position within the cell is crucial. Within cells, mitochondria are mobile via the cytoskeleton tracks (Lacker, 2013). Axonal mitochondria motility is regulated by intracellular and mitochondrial matrix Ca2+ concentration; the number of moving mitochondria in the axon is mediated primarily through neuronal activity (Obashi and Okabe, 2013). Morphologically, abnormal fission and fusion mitochondria, elongated and short round mitochondria, respectively, also cause distribution changes within the cell. These processes, as well as the cytoskeleton, play pivotal roles in maintaining cell integrity and therefore any changes in these processes can have drastic consequences, such as the neurodegeneration observed in AD (Bonda et al., 2010). Mitochondrial dysfunction in AD Aβ in mitochondria Aβ has recently been found in mitochondria (Picone et al., 2014), accumulating in post-mortem AD brains, AD brains of living patients and the brains of transgenic AD mice (Ankarcrona, Mangialasche and Winblad, 2010). Aβ is present in mitochondria prior to amyloid plaque formation, suggesting that mitochondria are early targets for Aβ aggregates and indicating that Aβ presence in mitochondria is an early stage of AD pathogenesis (Gillardon et al., 2007; Ankarcrona, Mangialasche and Winblad, 2010). While the exact mechanism of Aβ neurotoxicity remains largely unknown, Zhang et al. (2012) identified a single proapoptotic protein, a member of the mitochondrial solute carrier family (SLC25), which interacts with APP and is associated with the characteristic neurodegeneration observed in AD. This study was conducted in vitro using yeast-two-hybrid assays identifying the SLC25A38 protein, which was assigned the name appoptosin, as the link between APP interaction and neuronal apoptosis (Zhang et al., 2012). Until recently, there was no knowledge of the function of appoptosin. Guernsey et al. (2009) provided evidence that appoptosin is responsible for transporting glycine and 5-amino-levulinic acid (δ-ALA) across the mitochondria, vital for heme synthesis. A balance of free heme and protein-bound heme is maintained via homeostasis and maintains cell integrity. Alteration of this homeostatic balance can result in excess free heme which can lead to increased reactive oxygen species (ROS) and a destabilized mitochondrial cytoskeleton (Kumar and Bandyopadhyay, 2005), ultimately resulting in faulty heme metabolism. Appoptosin regulates intrinsic caspase-dependent apoptosis via heme biosynthesis, associating appoptosin with the neuronal death seen in AD and other neurodegenerative diseases (Zhang et al., 2012). Using cultured rat hippocampal neurons it has been demonstrated that on exposure to low sub-cytotoxic levels of Aβ, severe impairment of mitochondrial transport (Rui et al., 2006), increased mtDNA levels and increased numbers of malformed mitochondria can be observed (Diana et al., 2008). Aβ binds to the Aβ-binding alcohol dehydrogenase protein in mitochondria, and by blocking this interaction both neuronal apoptosis induced by Aβ and generation of free radicals in neurons can be suppressed (Lezi and Swerdlow, 2012). These findings have also been confirmed in AD studies with human participants (Lustbader et al., 2004; Caspersen et al., 2005; Crouch et al., 2005; Devi et al., 2006). The role of Aβ mitochondria has been investigated more since these studies, and research suggests that Aβ cannot be generated locally in mitochondria (Hansson-Peterson et al., 2008), therefore it must be taken up by the organelle from elsewhere inside the cell. Using isolated rat mitochondria, it was demonstrated that Aβ is internalized by cells from an extracellular source and then imported into the mitochondria via the translocase of the outer membrane complex before accumulating in the mitochondrial cristae (Hansson-Peterson et al., 2008). Oxidative stress Oxidative stress plays a key role not only in AD pathogenesis, but also in other neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease (Dias, Junn and Mouradian, 2013). The brain is particularly vulnerable to oxidative stress due its high oxygen demand, requiring 20% of the body's oxygen despite only making up approximately 2% of the body weight (Jain, Langham and Wehrli, 2010). In a 2-year study conducted from 2010 to 2012, a correlation was observed between oxidative stress and cognitive decline in AD in those aged 63–93 years, using glutathione as a biomarker for oxidative stress (Revel et al., 2015). DNA bases are particularly vulnerable to damage caused by oxidative stress, which can trigger excitotoxic responses ultimately resulting in cell death (Feng and Wang, 2012). As part of the electron transport chain (ETC), protons are pumped across the IMM from the mitochondrial matrix, resulting in a negative membrane potential across the IMM. This causes small numbers of electrons to slowly move out of the redox enzyme complexes (Ankarcrona, Mangialasche, and Winblad, 2010) in the IMM, which are capable of forming the superoxide radical (O2−), one of the main ROS, on interaction with oxygen molecules (Picone et al., 2014). Mitochondria encompass a widespread and intense antioxidant defence mechanism in order to destroy any ROS, such as the superoxide radical, that may be formed during normal respiration. Any damage to mitochondria can result in interrupting the usual mechanisms by which ROS are destroyed, therefore increasing the number of ROS present in the organelle (Picone et al., 2014). For example, it has been found that in post-mortem AD brains there is a deficit of cytochrome c oxidase (COX), the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, in the occipital, parietal, temporal and frontal lobes as well as in the hippocampus (Mutisya, Bowling, and Beal, 1994). This dysfunction forms a cycle in which mitochondria contain more ROS due to damage, which in turn results in more damage due to an increase in the number of ROS present and so on. Excess free radicals can cause various biochemical changes observed in neurodegeneration, such as lipid peroxidation (Padurariu et al., 2013). This results in cell damage and is responsible for some of the classic pathological changes observed in neurodegenerative disease. Oxidative stress has also been found to alter Aβ levels and tau phosphorylation, the two key hallmarks of AD, via the modification of signalling pathways. Tau phosphorylation is increased via the activation of glycogen synthase kinase 3-β during high levels of oxidative stress (Lovell et al., 2004), which also increases the expression of β-secretase (Tamagno et al., 2005) and upregulates Aβ. Discovery of this link between oxidative stress in mitochondria and AD has sparked research into potential new drug targets, aimed at both oxidative stress and ROS. Potential new treatment strategies Antioxidants Antioxidants bind with free radicals to diminish the latter's highly reactive and destructive properties and decrease the damage they cause. Antioxidants have been meticulously studied with regards to reducing mitochondrial toxicity caused by oxidative stress; however, even though there has been a great amount of research conducted in this area (Kumar and Singh, 2015) it has produced debatable results due to the low permeability of the blood brain barrier to many of the antioxidants used today (Picone et al., 2014). New treatment strategies targeting this limitation have recently been tested, such as those using nanoparticles in order to deliver a more successful route for antioxidant drugs entering the central nervous system (Gomes, Martins and Sarmento, 2015). Vitamin E is a generic term for a group of naturally occurring derivatives of tocopherol and tocotrienol, and is a crucial antioxidant in protecting cellular membranes such as those found in mitochondria (Ankarcrona, Mangialasche, and Winblad 2010). α-tocopherol (Toc) (Fig. 3A) is the most studied of these with regards to AD, and has been found to significantly slow the rate of cognitive decline in those with mild to moderate (Dysken et al., 2014), albeit not being specifically targeted at mitochondria. However, in a study on aged male C57BL/6 J mice, the supplementation of one antioxidant alone had little or no effect in increasing cognitive function and it was shown that age-related cognitive dysfunction could be reversed by supplementing the mice with Toc and Coenzyme Q10 (CoQ) (Fig. 4), involved naturally in the respiratory chain in combination (Shetty et al., 2014). Figure 3. Open in new tabDownload slide Chemical structures of α-tocopherol (A), Dimebon (B) and α-lipoic acid (C). Figure 4. Open in new tabDownload slide Chemical structure of coenzyme Q10. α-lipoic acid (LA) (Fig. 3B) is itself a powerful antioxidant which has the ability to recycle other antioxidants such as vitamins C and E. LA is a naturally occurring cofactor of mitochondrial enzymes α-ketoglutarate dehydrogenase and pyruvate dehydrogenase, and has been found to increase ACh production and scavenge the toxic products of lipid peroxidation (Maczurek et al., 2008). For more than 30 years, LA has been used in Germany as a treatment for diabetic polyneuropathy (Ziegler et al., 1999). However, it was not until an elderly patient already receiving LA treatment for diabetic polyneuropathy was diagnosed with early stage AD in 1997 that clinical trials began. When this patient was diagnosed with AD, AChEIs were prescribed as standard and her course of 600 mg per day of LA was continued. Over time her AD did not worsen as rapidly as expected, and her cognitive decline was found to be surprisingly slow (Hager et al., 2001). In the subsequent clinical trial conducted by Hager et al. (2001), nine patients with probable AD were given 600 mg of LA daily, as well as either donepezil or rivastigmine. Results demonstrated that cognitive decline was slowed in these patients after the LA was prescribed in comparison to AChEIs alone. Many naturally occurring antioxidants have been tested as therapies for AD; however, most have failed to improve cognitive function. Promising new mitochondria-targeted antioxidants have been manufactured as a result of this. One of these specific antioxidants is mitoquinone mesylate, more commonly known as MitoQ (McManus, Murphy and Franklin, 2011). MitoQ accumulates in vivo and was specifically designed to protect the mitochondrial membrane from the severe damage that can be caused by lipid peroxidation and oxidative stress (Smith et al., 2012). The main antioxidant component of MitoQ is ubiquinone, identical to the active antioxidant found in CoQ, which is selectively taken up by mitochondria due to the membrane potential produced, resulting in an almost thousand fold concentration of the drug inside the mitochondrial matrix (Ng et al., 2014). The synthesis of MitoQ is carried out by covalently binding the ubiquinone component to a cation called decyltriphenylphosphonium through a long aliphatic carbon chain. The ubiquinone is then introduced to the lipid bilayer of the mitochondrial matrix where it is reduced rapidly to a product known as ubiquinol, the active antioxidant of MitoQ. This ubiquinol, once introduced, is recycled continuously via the ETC (Ng et al., 2014) (Fig. 5). Since MitoQ is found in such high concentrations within the mitochondria, it is able to neutralize free radicals before they even reach their targets and thus drastically reduces the damage that these free radicals may cause (Picone et al., 2014). Ng et al. (2014) treated transgenic Caenorhabditis elegans overexpressing human Aβ peptide, which leads to progressive paralysis in C. elegans, with MitoQ of varying concentrations in a blinded dose-response study. It was found that when administered both 1 and 5 µM MitoQ, C. elegans had significantly longer lifespans when compared to an untreated control. It was also found in a study by McManus, Murphy and Franklin (2011) that MitoQ had positive effects in a triple transgenic mouse model of AD, where MitoQ was able to prevent cognitive decline, oxidative stress, Aβ accumulation and synaptic loss in the brains of the mice. Figure 5. Open in new tabDownload slide Mechanism of MitoQ entering the cell and the mitochondria, with the recycling of MitoQ via the ETC displayed. (Reproduced from MitoQ.com, open access under the Creative Commons Attribution License CC-BY-SA 3.0.) Though this research has so far only been conducted in transgenic mouse models and C elegans, it demonstrates that mitochondria-targeted antioxidants such as MitoQ could have improved therapeutic potential when compared to natural antioxidants, and therefore could be successful treatment strategies with regards to AD and similar neurodegenerative diseases in the future. Dimebon (Latrepirdine) Latrepirdine, sold as dimebon (Fig. 3C), is a drug that has been used clinically in Russia as a non-selective antihistamine for skin allergies and allergic rhinitis since 1983 (Ankarcrona, Mangialasche and Winblad, 2010), but was withdrawn to be used for more selective treatments. The exact mechanism by which dimebon works is not yet known (Perez et al., 2012); however, in several in vitro studies, dimebon has shown to be neuroprotective against Aβ25-35 β-amyloid fragments in cerebellar granule cell cultures, designed to mimic the neurodegeneration found in the likes of AD (Bachurin et al., 2001; Lermontova et al., 2001). Dimebon has also been found to be a weak AChEI, with a half maximal inhibitory concentration (IC50) of 8–42 µM (Bachurin et al., 2001; Schaffhauser et al., 2009). It has also proved to be a weak NMDA receptor antagonist (IC50 = 10 µM) (Grigorev, Dranyi and Bachurin, 2003; Schaffhauser et al., 2009) and a weak inhibitor of voltage-gated Ca2+ channels (IC50 = 50 µM) (Lermontova et al., 2001; Schaffhauser et al., 2009). At an optimum concentration of 10 µM, dimebon has an inhibitory effect of more than 50% on a total of 18 receptors, including several serotonin receptors (Schaffhauser et al., 2009). The main component of the tau inclusions found in frontotemporal lobar degeneration, a form of dementia similar to AD characterized by severe muscle wasting, is a protein known as transactivation responsive DNA binding protein of 43 kDa (TDP-43) (Yamashita et al., 2009). This protein inclusion has also been found in a subpopulation of patients with other neurodegenerative diseases such as AD and dementia with Lewy bodies (Arai et al., 2009) as well as Huntington's disease (Schwab et al., 2008). In an in vitro study conducted on neuroblastoma SH-SY5Y cells expressing mutated TDP-43, it was found that 5 µM concentrations of dimebon over a 3-day incubation period reduced the number of TDP-43 aggregates by 45% when compared to controls (Yamashita et al., 2009), suggesting that dimebon possesses anti-oligomerization properties. Numerous trials have been conducted using dimebon as a possible therapy for AD, as was carried out by Doody et al. (2008). In this randomized, double-blind, placebo-controlled phase II trial, 183 Russian patients with mild to moderate AD were randomly assigned either 60 mg of dimebon per day or a matched placebo. Results showed a significant improvement in cognitive function and a significantly increased score on CFTs in the dimebon group compared to the placebo (Doody et al., 2008). These findings showed promise for dimebon as a potential AD therapy, sparking further study. Thus, an international double-blind phase III CONNECTION trial was conducted in 2010 using 598 participants from North America, South America and Europe. When dimebon was compared to a placebo group over a 6-month period, patients with mild to moderate AD did not show a statistically higher performance on any CFTs, and therefore dimebon did not meet CONNECTIONs co-primary (cognition and global function) or secondary efficacy end points (Pfizer Inc. and Medivation Inc., 2010). The plausibility of dimebon has been questioned by some as a treatment for AD, and it is not yet Food and Drug Administration approved as an AD treatment. Further phase III trials are ongoing in an attempt to replicate the findings of Doody et al.’s (2008) study. One randomized, double-blind, placebo-controlled phase III trial known as CONCERT enrolled approximately 1050 participants with mild to moderate AD from numerous sites across Western Europe, USA, Australia and New Zealand to participate in a 12-month study, designed to evaluate the efficacy of dimebon when added to ongoing AD treatment with donepezil (Pfizer Inc. and Medivation Inc., 2015). The results of this trial were unfortunately negative yet again, which proves detrimental for dimebon as an AD therapy, and further highlights the difficulties scientists face in finding potential treatments for diseases like AD. Conclusion Mitochondrial dysfunction is an early feature of AD pathology. Any damage to mitochondria by either Aβ or ROS can result in interrupting the usual mechanisms by which ROS are destroyed, therefore further increasing the number of ROS present in the organelle. It has been found that in post-mortem AD brains there is a deficit of COX, the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, supporting the theory that ROS are involved in the mitochondrial damage found in AD. Many antioxidants have been investigated as therapies for AD, and further studies have been carried out to find mitochondria specific antioxidants to enable a greater concentration of antioxidants to accumulate in the mitochondria, allowing a more specific method for combatting mitochondrial oxidative stress. It has been suggested that as early as 2025, prevention or effective treatment of AD may be realized (Cummings et al., 2016). Steps along this road include finding therapies that inhibit primary progenitors, reduce secondary symptoms, slow AD progression and ultimately repair damaged neurons (Feng and Wang, 2012). Further study of both generic and mitochondria specific antioxidants should be carried out to find more potential treatment strategies for Aβ induced neurotoxicity in AD and other neurodegenerative diseases. Acknowledgements Many thanks to Jane Armstrong, Mark Davies and Nicolas Haroune for helpful comments on earlier drafts of this work. Author biography Zoe L. Hawking recently graduated the University of Sunderland's BSc Biomedical Sciences degree in July 2016 with a first class honours. This review is largely unmodified from her level 5 biosciences literature review. Zoe has particular interests in both Alzheimer's disease and cancer and hopes to pursue a career in cancer biology. References Annamalai , B. , Won , J. S., Choi , S. et al. . ( 2015 ) Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation , Biochemical and Biophysical Research Communications , 29 ( 15 ), 132 – 141 . Google Scholar OpenURL Placeholder Text WorldCat Ankarcrona , M. , Mangialasche , F. and Winblad , B. ( 2010 ) Rethinking Alzheimer's disease therapy: are mitochondria the key . Journal of Alzheimer's Disease , 20 ( 2 ), 579 – 590 . Google Scholar OpenURL Placeholder Text WorldCat Arai , T. , MacKenzie , I. R., Hasegawa , M. et al. . ( 2009 ) Phosphorylated TDP-43 in Alzheimer's disease and dementia with lewy bodies , Acta Neuropathologica , 117 ( 2 ), 125 – 136 . Google Scholar Crossref Search ADS PubMed WorldCat Bachurin , S. O. , Bukatina , E., Lermontova , N. N. et al. . ( 2001 ) Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer , Annals of the New York Academy of Sciences , 939 , 425 – 435 . Google Scholar Crossref Search ADS PubMed WorldCat Biswas , J. , Goswami , P., Gupta , S. et al. . ( 2015 ) Streptozotocin induced neurotoxicity involves Alzheimer's related pathological markers: a study on N2A cells , Molecular Neurobiology . DOI:10.1007/s12035-015-9144-z. Google Scholar OpenURL Placeholder Text WorldCat Bonda , D. J. , Wang , X., Perry , G. et al. . ( 2010 ) Mitochondrial dynamics in Alzheimer's disease: opportunities for future treatment strategies , Drugs Aging , 27 ( 3 ), 181 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat Brunstromm , H. R. and Englund , E. M. ( 2009 ) Cause of death in patients with dementia disorders , European Journal of Neurology , 16 ( 4 ), 488 – 492 . Google Scholar Crossref Search ADS PubMed WorldCat Cacabelos , R . ( 2007 ) Donepezil in Alzheimer's disease: from conventional trials to pharmacogenetics , Neuropsychiatric Disease Treatment , 3 ( 3 ), 303 – 333 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Caspersen , C. , Wang , N., Yao , J. et al. . ( 2005 ) Mitochondrial abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease , The Journal of the Federation of American Societies for Experimental Biology (FASEB) , 19 ( 14 ), 2040 – 2041 . Google Scholar OpenURL Placeholder Text WorldCat Centers for Disease Control and Prevention, National Center for Health Statistics . Available at: http://wonder.cdc.gov/ucd-icd10.html [Accessed: 24 February 2015]. Chan , D. C . ( 2006 ) Mitochondrial fusion and fission in mammals , Annual Review of Cell and Developmental Biology , 22 , 79 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat Christiane , R. , Brayne , C. and Mayeux , R. ( 2011 ) Epidemiology of Alzheimer Disease , Nature Reviews Neurology , 7 ( 3 ), 137 – 152 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Crouch , P. J. , Blake , R., Duce , J. A. et al. . ( 2005 ) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta 1-42 , Journal of Neuroscience , 25 ( 3 ), 672 – 679 . Google Scholar Crossref Search ADS PubMed WorldCat Cullen , B. , O'Neill , B., Evans , J. J. et al. . ( 2007 ) A review of screening tests for cognitive impairment , Journal of Neurology, Neurosurgery and Psychiatry , 78 ( 8 ), 790 – 799 . Google Scholar Crossref Search ADS WorldCat Cummings , J. , Aisen , P. S., DuBois , B. et al. . ( 2016 ) Drug development in Alzheimer's disease: the path to 2025 , Alzheimer's Research and Therapy , 8 ( 1 ), 39 . Google Scholar Crossref Search ADS PubMed WorldCat Das , P. , Murray , B. and Belfort , G. ( 2015 ) Alzheimer's protective A2T mutation changes the conformational landscape of the Aβ1-42 monomer differently than does the A2V mutation , Biophysical Journal , 108 ( 3 ), 738 – 747 . Google Scholar Crossref Search ADS PubMed WorldCat Department of Economic and Social Affairs . ( 2001 ) World Population Ageing: 1950–2050 , USA, United Nations , New York . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Devi , L. , Prabhu , B. M., Galati , D. F. et al. . ( 2006 ) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction , Journal of Neuroscience , 26 ( 35 ), 9057 – 9068 . Google Scholar Crossref Search ADS PubMed WorldCat Diana , A. , Simic , G., Sinforiani , E. et al. . ( 2008 ) Mitochondria morphology and DNA content upon sublethal exposure to beta-amyloid (1-42) peptide , Collegium Antropologicum , 32 ( 1 ), 51 – 58 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Dias , V. , Junn , E., Mouradian , M. M. ( 2013 ) The role of oxidative stress in Parkinson's Disease , Journal of Parkinson's Disease , 3 ( 4 ), 461 – 491 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Doody , R. S. , Gavrilova , S. I., Sano , M. et al. . ( 2008 ) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , Lancet , 372 ( 9634 ), 207 – 215 . Google Scholar Crossref Search ADS PubMed WorldCat Dysken , M. W. , Sano , M., Asthana , S. et al. . ( 2014 ) Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial , The Journal of the American Medical Association , 311 ( 1 ), 33 – 44 . Google Scholar Crossref Search ADS PubMed WorldCat Fargo , K. N. , Aisen , P., Albert , M. et al. . ( 2014 ) 2014 report on the milestones for the US national plan to address Alzheimer's disease , The Journal of the Alzheimer's Association , 10 ( 5 ), 430 – 452 . Google Scholar Crossref Search ADS WorldCat Farlow , M. R. , Sadowsky , C. H., Velting , D. M. et al. . ( 2015 ) Evaluating response to high-dose 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease , CNS Neuroscience and Therapeutics , 21 ( 6 ), 513 – 519 . Google Scholar Crossref Search ADS PubMed WorldCat Farokhnia , M. , Sabet , M. S., Iranpour , N. et al. . ( 2014 ) Comparing the efficacy and safety of Crocus Sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial , Human Psychopharmacology: Clinical and Experimental , 29 , 351 – 359 . Google Scholar Crossref Search ADS WorldCat Feng , Y. and Wang , X. ( 2012 ) Antioxidant therapies for Alzheimer's disease , Oxidative Medicine and Cellular Longevity , 2012 , 1 – 17 . Google Scholar Crossref Search ADS WorldCat Gillardon , F. , Rist , W., Kussmaul , L. et al. . ( 2007 ) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition , Proteomics , 7 ( 4 ), 605 – 616 . Google Scholar Crossref Search ADS PubMed WorldCat Gomes , M. J. , Martins , S. and Sarmento , B. ( 2015 ) siRNA as a tool to improve the treatment of brain diseases: mechanism, targets and delivery , Ageing Research Reviews , 21 , 43 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Grigorev , V. V. , Dranyi , O. A. and Bachurin , S. O. ( 2003 ) Comparative study of reaction mechanisms of dimebon and memantine on AMPA- and NDMA-subtypes glutamate receptors in rat cerebral neurons , Bulletin of Experimental Biology and Medicine , 136 ( 5 ), 474 – 477 . Google Scholar Crossref Search ADS PubMed WorldCat Guernsey , D. L. , Jiang , H., Campagna , D. R. et al. . ( 2009 ) Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia , Nature Genetics , 41 ( 6 ), 651 – 653 . Google Scholar Crossref Search ADS PubMed WorldCat Guzman-Martinez , L. , Farias , G. A. and Maccioni , R. B. ( 2013 ) Tau oligomers as potential targets for Alzheimer's disease and novel drugs , Frontiers in Neurology , 4 , 167 . Google Scholar Crossref Search ADS PubMed WorldCat Hager , K. , Marahrens , A., Kenklies , M. et al. . ( 2001 ) Alpha-lipoic acid as a new treatment option for Alzheimer type dementia , Archives of Gerontology and Geriatrics , 32 ( 3 ), 275 – 282 . Google Scholar Crossref Search ADS PubMed WorldCat Hansson-Peterson , C. A. , Alikhani , H., Behbahani , H. et al. . ( 2008 ) The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae , Proceedings of the National Academy of Sciences of the United States of America , 105 ( 35 ), 13145 – 13150 . Google Scholar Crossref Search ADS PubMed WorldCat Hayden , E. Y. and Teplow , D. B. ( 2013 ) Amyloid β-protein oligomers and Alzheimer's disease , Alzheimer's Research and Therapy , 5 ( 6 ), 60 . Google Scholar Crossref Search ADS PubMed WorldCat Herholz , K . ( 2008 ) Acetylcholinesterase activity in mild cognitive impairment and Alzheimer's disease , European Journal of Nuclear Medicine and Molecular Imaging , 35 ( 1 ), 25 – 29 . Google Scholar Crossref Search ADS WorldCat Hurd , M. D. , Martorell , P., Delavande , A. et al. . ( 2013 ) Monetary costs of dementia in the United States , The New England Journal of Medicine , 368 ( 14 ), 1326 – 1334 . Google Scholar Crossref Search ADS PubMed WorldCat Jain , V. , Langham , M. C. and Wehrli , F. W. ( 2010 ) MRI estimation of global brain oxygen consumption rate , Journal of Cerebral Blood Flow and Metabolism , 30 ( 9 ), 1598 – 1607 . Google Scholar Crossref Search ADS PubMed WorldCat Knott , A. B. and Bossy-Wetzel , E. ( 2008 ) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration , Annals of the New York Academy of Sciences , 1147 , 283 – 292 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , S. and Bandyopadhyay , U. ( 2005 ) Free heme toxicity and its detoxification systems in human , Toxicology Letters , 157 ( 3 ), 175 – 188 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , A. and Singh , A. ( 2015 ) A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions , Frontiers in Pharmacology , 6 , 206 . Google Scholar Crossref Search ADS PubMed WorldCat Lacker , L. L . ( 2013 ) Determining the shape and cellular distribution of mitochondria: the integration of multiple activities , Current Opinion in Cell Biology , 25 ( 4 ), 471 – 476 . Google Scholar Crossref Search ADS PubMed WorldCat Leifer , B. P . ( 2009 ) Alzheimer's disease: seeing the signs early , Journal of the American Academy of Nurse Practitioners , 21 ( 11 ), 588 – 595 . Google Scholar Crossref Search ADS PubMed WorldCat Lermontova , N. N. , Redkozubov , A. E., Shevstova , E. F. et al. . ( 2001 ) dimebon and tacrine inhibit neurotoxic action of beta-amyloid culture and block L-Type Ca2+ channels , Bulletin of Experimental Biology and Medicine , 132 ( 5 ), 1079 – 1083 . Google Scholar Crossref Search ADS PubMed WorldCat Lezi , E. and Swerdlow , R. H. ( 2012 ) Mitochondria in neurodegeneration , Advances in Experimental Medicine and Biology , 942 , 269 – 286 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lovell , M. A. , Xiong , S., Xie , C. et al. . ( 2004 ) Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3 , Journal of Alzheimer's Disease , 6 ( 6 ), 659 – 671 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lustbader , J. W. , Cirilli , M., Lin , C. et al. . ( 2004 ) ABAD directly links abeta to mitochondrial toxicity in Alzheimer's disease , Science , 304 ( 5669 ), 448 – 452 . Google Scholar Crossref Search ADS PubMed WorldCat Maczurek , A. , Hager , K., Kenklies , M. et al. . ( 2008 ) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease , Advanced Drug Delivery Reviews , 60 ( 13-14 ), 1463 – 1470 . Google Scholar Crossref Search ADS PubMed WorldCat Mandemakers , W. , Morais , V. A. and De Strooper , B. ( 2007 ) A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases , Journal of Cell Science , 120 ( 10 ), 1707 – 1716 . Google Scholar Crossref Search ADS PubMed WorldCat Mantoani , S. P. , Chierrito , T. P., Vilela , A. F. et al. . ( 2016 ) Novel triazole-quinoline derivatives as selective dual binding site acetylcholinesterase inhibitors , Molecules , 21 ( 2 ), 193 . Google Scholar Crossref Search ADS WorldCat McManus , M. J. , Murphy , M. P. and Franklin , J. L. ( 2011 ) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathy in a transgenic mouse model of Alzheimer's disease , Journal of Neuroscience , 31 ( 44 ), 15703 – 15715 . Google Scholar Crossref Search ADS PubMed WorldCat Menting , K. W. and Claassen , J. A. H. R. ( 2014 ) β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease , Frontiers in Ageing Neuroscience , 6 ( 165 ). 10.3389/fnagi.2014.00165. Google Scholar OpenURL Placeholder Text WorldCat Mitoq.com . MitoQ. [Image] [Online] Available at: http://commons.wikimedia.org/wiki/File%3AMitoq_Accumulation.jpg [Accessed: 7 April 2015]. Mohammadi-Khanaposhtani , M. , Saeedi , M., Zafarghandi , N. S. et al. . ( 2015 ) Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation and docking study of acridone linked to 1,2,3-triazole derivatives , European Journal of Medical Chemistry , 92 , 799 – 806 . Google Scholar Crossref Search ADS WorldCat Mushtag , G. , Greig , N. H., Khan , J. A. et al. . ( 2014 ) Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus , CNS & Neurological Disorders Drug Targets , 13 ( 8 ), 1432 – 1439 . Google Scholar Crossref Search ADS PubMed WorldCat Mutisya , E. M. , Bowling , A. C. and Beal , M. F. ( 1994 ) Cortical cytochrome oxidase activity is reduced in Alzheimer's disease , Journal of Neurochemistry , 63 ( 6 ), 2179 – 2184 . Google Scholar Crossref Search ADS PubMed WorldCat Ng , L. F. , Gruber , J., Cheah , I. K. et al. . ( 2014 ) The mitochondria targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease , Free Radical Biology and Medicine , 71 , 390 – 401 . Google Scholar Crossref Search ADS PubMed WorldCat NHS UK , 2015 . Tests for Diagnosing Dementia. [Online] Available at: http://www.nhs.uk/conditions/dementia-guide/pages/dementia-diagnosis-tests.aspx [Accessed: 1 December 2015]. Obashi , K. and Okabe , S. ( 2013 ) Regulation of mitochondrial dynamics and distribution by synapse position and neuronal activity in the axon , European Journal of Neuroscience , 38 ( 3 ), 2350 – 2363 . Google Scholar Crossref Search ADS PubMed WorldCat Obregon , D. , Hou , H., Deng , J. et al. . ( 2012 ) sAPP-α modulates β-secretase activity and amyloid-β generation , Nature Communications , 10 ( 3 ), 777 . Google Scholar Crossref Search ADS WorldCat O'Brien , R. J. and Wong , P. C. ( 2011 ) Amyloid precursor protein processing and Alzheimer's disease , Annual Review of Neuroscience , 34 , 185 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat Obulesu , M. and Lakshmi , M. J. ( 2014 ) Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues , Neurochemical Research , 39 ( 12 ), 2301 – 2312 . Google Scholar Crossref Search ADS PubMed WorldCat Padurariu , M. , Ciobica , A., Lefter , R. et al. . ( 2013 ) The oxidative , Stress Hypothesis in Alzheimer's Disease , 25 ( 4 ), 401 – 409 . Google Scholar OpenURL Placeholder Text WorldCat Perez , S. E. , Nadeem , M., Sadleir , K. R. et al. . ( 2012 ) Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice , International Journal of Physiology, Pathophysiology and Pharmacology , 4 ( 3 ), 115 – 127 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Picone , P. , Nuzzo , D., Caruana , L. et al. . ( 2014 ) Mitochondrial dysfunction: different routes to Alzheimer's disease therapy , Oxidative Medicine and Cellular Longevity , 2014 , 1 – 11 . Google Scholar Crossref Search ADS WorldCat Pfizer Press Inc. and Medivation Inc . ( 2010 ). Pfizer and medivation announce results from two phase 3 studies in Dimebon (Latrepirdine*) Alzheimer's disease clinical development program. [Online] Available at: http://investors.medivation.com/releasedetail.cfm?releaseID=448818 [Accessed: 10 April 2015]. Pfizer Press Inc. and Medivation Inc . ( 2015 ). Pfizer and medivation initiate phase 3 trial of dimebon added to donepezil in patients with Alzheimer's disease. [Online] Available at: http://www.prnewswire.com/news-releases/pfizer-and-medivation-initiate-phase-3-trial-of-dimebon-added-to-donepezil-in-patients-with-alzheimers-disease-61820322.html [Accessed: 19 April 2015]. Qiu , C. , Kivipelto , M. and von Strauss , E. ( 2009 ) Epidemiology of Alzheimer's disease: occurrence, determinants and strategies toward intervention , Dialogues in Clinical Neuroscience , 11 ( 2 ), 111 – 128 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Revel , F. , Gilbert , T., Roche , S. et al. . ( 2015 ) Influence of oxidative stress on cognitive decline , Journal of Alzheimer's Disease , 45 ( 2 ), 553 – 560 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Rui , Y. , Tiwari , P., Xie , Z. et al. . ( 2006 ) Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons , Journal of Neuroscience , 26 ( 41 ), 10480 – 10487 . Google Scholar Crossref Search ADS PubMed WorldCat Sadowsky , C. H. , Micca , J. L., Grossberg , G. T. et al. . ( 2014 ) Rivastigmine from capsule to patch: therapeutci advances in the management of Alzheimer's disease and Parkinson's disease dementia , The Primary Care Companion for CNS Disorders , 16 ( 5 ), 1654 – 1662 . Google Scholar OpenURL Placeholder Text WorldCat Santos , R. X. , Correia , S. C., Wang , X. et al. . ( 2010 ) a synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease , Journal of Alzheimer's Disease: JAD , 20 ( 2 ), 401 – 412 . Google Scholar OpenURL Placeholder Text WorldCat Sasaki , S. and Horie , Y. ( 2014 ) The effects of an uninterrupted switch from donepezil to galantamine without dose titration on behavioral and psychological symptoms of dementia in Alzheimer's disease , Dementia and Geriatric Cognitive Disorders Extra , 4 ( 2 ), 131 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat Schaffhauser , H. , Mathiasen , J. R., DiCamillo , A. et al. . ( 2009 ) Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities , Biochemical Pharmacology , 78 ( 8 ), 1035 – 1042 . Google Scholar Crossref Search ADS PubMed WorldCat Schwab , C. , Arai , T., Hasegawa , M. et al. . ( 2008 ) Colocalization of transactivation-responsive DNA binding protein 43 and huntingtin in inclusions of huntington disease , Journal of Neuropathology and Experimental Neurology , 67 ( 12 ), 1159 – 1165 . Google Scholar Crossref Search ADS PubMed WorldCat Shetty , R. A. , Ikonne , U. S., Forster , M. J. and Sumien , N. ( 2014 ) Coenzyme Q10 and α-tocopherol reversed age-associated functional impairments in mice , Experimental Gerontology , 2014 , 208 – 218 . Google Scholar Crossref Search ADS WorldCat Smith , R. A. , Hartley , R. C., Cocheme , H. M. et al. . ( 2012 ) Mitochondrial pharmacology , Trends in Pharmacological Sciences , 33 , 341 – 352 . Google Scholar Crossref Search ADS PubMed WorldCat Sperling , R. A. , Aisen , P. S., Beckett , L. A. et al. . ( 2011 ) Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , Alzheimer's & Dementia , 7 ( 3 ), 280 – 292 . Google Scholar Crossref Search ADS WorldCat Tamagno , E. , Parola , M., Bardini , P. et al. . ( 2005 ) β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress activated protein kinases pathways , Journal of Neurochemistry , 92 ( 3 ), 628 – 636 . Google Scholar Crossref Search ADS PubMed WorldCat Walsh , D. M. and Selkoe , D. J. ( 2007 ) Aβ oligomers: a decade of discovery , Journal of Neurochemistry , 101 ( 5 ), 1172 – 1184 . Google Scholar Crossref Search ADS PubMed WorldCat Wang , X. , Su , B., Zheng , L. et al. . ( 2009 ) The role of mitochondrial dynamics in the pathogenesis of Alzheimer's disease , Journal of Neurochemistry , 109 , 153 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat Wenk , G. L. , Parsons , C. G. and Danysz , W. ( 2006 ) Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine , Behavioural Pharmacology , 17 , 411 – 424 . Google Scholar Crossref Search ADS PubMed WorldCat Yamashita , M. , Nonaka , T., Arai , T. et al. . ( 2009 ) Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models , FEBS Letters , 583 ( 14 ), 2419 – 2424 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , H. , Zhang. , Y., Chen , Y. et al. . ( 2012 ) Appoptosin is a novel proapoptotic protein and mediates cell death in neurodegeneration , The Journal of Neuroscience , 32 ( 44 ), 15565 – 15576 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , Y. , Thompson , R., Zhang , H. et al. . ( 2011 ) APP processing in Alzheimer's disease , Molecular Brain, 4 (3) . DOI:10.1186/1756-6606-4-3. Google Scholar OpenURL Placeholder Text WorldCat Zhou , A. , Wu , H., Pan , J. et al. . ( 2015 ) Synthesis and evolution of paeonol derivatives as potential multifunctional agents for the treatments of Alzheimer's disease , Molecules , 20 ( 1 ), 1304 – 1318 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu , M. , Xiao , S., Li , G. et al. . ( 2013 ) Effectiveness and safety of generic memantine hydrochloride manufactured in china in the treatment of moderate to severe Alzheimer's disease: a multicenter, double-blind randomized controlled trial , Shanghai Archives of Psychiatry , 25 ( 4 ), 244 – 253 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Ziegler , D. , Reljanovic , M., Mehnert , H. et al. . ( 1999 ) Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials , Experimental and Clinical Endocrinology & Diabetes , 107 ( 7 ), 421 – 430 . Google Scholar Crossref Search ADS WorldCat Author notes † Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author 2016. Published by Oxford University Press. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BioScience Horizons Oxford University Press

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

BioScience Horizons , Volume 9 – Jan 1, 2016

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

BioScience Horizons , Volume 9 – Jan 1, 2016

Abstract

Abstract Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD. As these drugs simply delay the onset of symptoms, the development of new therapies is key. As neurons are highly energy-demanding cells, they rely heavily on the functions of mitochondria, and any dysfunction affecting respiratory processes can be devastating and lead to the neuronal death characteristic of AD. Dysfunction in fission and fusion processes of mitochondria have been observed in early AD and are heavily involved in AD pathogenesis. Beta-amyloid (Aβ) is a neurotoxic protein formed in the AD brain as a result of inappropriate secretase activity and is one of the major hallmarks of the disease. Aβ has recently been discovered in the membranes of mitochondria, disabling many basic respiratory functions. Ongoing research is largely targeted at protecting mitochondria from damage caused by factors such as Aβ and oxidative stress. Antioxidants have been meticulously studied, and several generic antioxidants such as α-tocopherol have been found to significantly slow the rate of cognitive decline in both mild to moderate and severe AD. MitoQ is a mitochondria specific antioxidant which is able to enter mitochondria in an almost thousand fold greater concentration than is achieved by generic antioxidants. This enables protection against potentially devastating factors for mitochondria, such as lipid peroxidation, oxidative stress and Aβ neurotoxicity. This review further discusses mitochondrial therapies as well as other new treatments for AD. β-amyloid, acetylcholine, mitochondria, MitoQ, antioxidants, reactive oxygen species (ROS) Introduction Alzheimer's disease (AD) is the leading cause of dementia worldwide. Dementia patients totalled 24.2 million in 2005 and 4.2 million cases arose each year from 2005 to 2011, with 70% of these cases being a result of AD (Christiane, Brayne and Mayeux, 2011). AD predominantly affects more women than men, and the number of people dying as a result of the disease increased by 55.7 people per hundred thousand in the USA from 2000 to 2010 (Centers for Disease Control and Prevention, NCHS, 2008). Frequently, the cause of death of AD sufferers is a secondary condition such as pneumonia or ischaemic heart disease which can be exacerbated by many of the symptoms of AD (Brunnstrom and Englund, 2009). The number of people developing AD is expected to triple by the year 2050 (Mohammadi-Khanaposhtani et al., 2015), when it is estimated that 4.1% of the population will be over 80 years of age (Department of Economic and Social Affairs, 2001). In developed countries, 1 in 10 people over the age of 65 are affected by dementia of some form, with the frequency of AD almost doubling within this specific population every 5 years (Qiu, Kivipelto and von Strauss, 2009). Worldwide, the cost of medical care for dementia sufferers totals approximately 604 billion US$ (Fargo et al., 2014), with the annual cost of AD per patient ranging from between US$42 000 and US$56 000 in the USA (Hurd et al., 2013). Clearly AD is both widespread and costly. AD is a progressive, age-associated neurodegenerative disease which is characterized by neuronal loss and accompanying cognitive impairment (Walsh and Selkoe, 2007; Bonda et al., 2010), with symptoms ranging from ‘preclinical’ (Sperling et al., 2011) to severe. Early symptoms of AD may first be mistaken by friends and family members as normal signs of ageing, however as the disease progresses symptoms worsen rapidly, though the rate at which this happens differs between individuals. Later stages of the disease result in the sufferer being unable to perform everyday tasks such as carrying out basic hygiene routines, or being able to bathe or eat independently (Leifer, 2009). AD commonly goes undiagnosed until it reaches these more debilitating stages. The mini mental state examination is used to assess the level of cognitive impairment that a dementia patient may be experiencing via a series of exercises, such as memorizing a list of objects or correctly answering time-orientation questions (NHS-UK, 2015). Further tests such as blood tests and MRI or CT scans may then be taken, characteristically showing diminished brain tissue as a result of neuronal loss, forming a definitive diagnosis (Cullen et al., 2007). The most popular theory regarding AD onset is the role of Aβ, a fundamental component of extracellular plaques that accumulate in the brains of AD sufferers via amyloidogenesis (Picone et al., 2014). This process is known to be a leading cause of the neuronal loss that can be observed in AD and is a recognized hallmark of the disease (Bonda et al., 2010; Das, Murray and Belfort, 2015). Similarly, microtubule associated tau proteins become hyperphosphorylated and form neurofibrillary tangles which is also recognized as a hallmark of the disease (Bonda et al., 2010; Annamalai et al., 2015). It is thought that as well as these known hallmarks, mitochondrial malfunctions play a distinct role in AD pathogenesis (Obulesu and Lakshmi, 2014). The processes of fission and fusion are vital in mitochondrial dynamics in order to maintain a balance of the morphology, number, distribution, and function of these organelles within cells (Wang et al., 2009). When these processes become unbalanced, mitochondria are unable to adequately carry out their functions making them vulnerable to consequences such as oxidative stress which can lead to the neurodegeneration typically seen in AD (Bonda et al., 2010). This review will outline the pathophysiology of AD and the current medications used, and primarily focus on newer treatment strategies such as therapies targeted at mitochondrial dysfunction in neurons. It will explain the possible benefits of these newer treatment techniques, currently undergoing clinical testing, and demonstrate the difficulties associated with finding successful AD therapies. Pathophysiology of AD and currently available medications Pathophysiology of AD Amyloid precursor protein (APP) is a type I transmembrane protein which is synthesized in the endoplasmic reticulum (O'Brien and Wong, 2011) and found in the neuronal cell membrane, with a large extracellular N-terminus and a shorter intracellular C-terminus. APP must be cleaved into smaller fragments by proteases in order to be functional. In healthy brains, a protease known as α-secretase carries out the first cleavage followed by a secondary cleavage from γ-secretase, giving rise to the nonamyloidgenic pathway. This forms the alpha C-terminal fragment and also causes APP to release its extracellular domain, known as APPsα (Obregon et al., 2012), which are thought to be beneficial to neurons (Zhang et al., 2011). In AD, APP is formed incorrectly due to an excess of β-secretase. When APP is first cleaved by β-secretase as opposed to α-secretase, C-terminal fragment β-CTF along with the soluble N-terminal fragment APPsβ are generated. γ-secretase further processes the β-CTF fragment, forming Aβ fragments of varying lengths; Aβ40 and Aβ42 being the primary toxic species found in AD brains (Obregon et al., 2012). This is known as the amyloidgenic pathway (Obregon et al., 2012; Picone et al., 2014) (Fig. 1). As more Aβ40 and Aβ42 are released, the Aβ oligomers increase in size and become insoluble and increasingly toxic to neurons, forming the aforementioned Aβ plaques (Hayden and Teplow, 2013). Figure 1. Open in new tabDownload slide Nonamyloidgenic and amyloidgenic pathways originate from different APP processing. The nonamyloidgenic pathway sees cleavage of α-secretase produce the healthy APPsα fragment, with further cleavage of γ-secretase giving rise to no Aβ generation. In AD, β-secretase forms the initial cleavage producing the APPsβ fragment, with γ-secretase combining to produce Aβ plaques in the amyloidgenic pathway. (Reproduced from Menting and Claassen 2014, open access under the Creative Commons Attribution License CC-BY.) In the brains of healthy individuals, tau stabilizes components critical to the internal transport system of neurons. Tau attaches to microtubules along the length of the neuron, allowing nutrients and other metabolic substances to be transported throughout the cell (Guzman-Martinez, Farias and Maccioni, 2013). In AD brains, tau is modified, causing it to separate from the microtubules therefore resulting in their degradation. Intracellular tangles formed by tau protein hyperphosphorylation disable the transport system and inactivate the neuron. Neurons are unable to regenerate, therefore as these processes continue neurons begin to disconnect from each other and eventually die, leading to memory loss, cognitive decline and other symptoms associated with AD as the brain tissue gradually shrinks and loses function. In AD patients, cholinergic pathways become compromised in the basal forebrain and cerebral cortex (Herholz, 2008), primarily due to an excess amount of acetylcholinesterase (AChE), leading to a decrease in acetylcholine (ACh) levels (Zhou et al., 2015). These cholinergic deficits are thought by many to be a major factor in AD (Herholz, 2008; Biswas et al., 2015; Zhou et al., 2015). Evidence suggests that AChE can also interact with Aβ and increase the number and toxicity of Aβ plaques via interaction with AChEs peripheral binding site (Mantoani et al., 2016). Currently available medications to target neurotransmitters ACh has been found to be greatly reduced in sufferers of AD compared to healthy controls (Ankarcrona, Mangialasche and Winblad, 2010; Zhou et al., 2015). Drugs currently available on the UK National Health Service work primarily by reducing AChE levels and therefore restoring levels of cholinergic transmission in the brain. Drugs can also be prescribed which target glutamatergic transmission, as both glutamatergic and cholinergic transmission are impaired in the brains of AD sufferers (Cacabelos, 2007). There are four main drugs currently in use for the relief of symptoms of AD: donepezil, rivastigmine, galantamine and, usually only prescribed for severe AD, memantine. Donepezil is the most commonly prescribed drug for AD in more than 50 countries. It is a highly selective AChE inhibitor (AChEI) with a response rate of 40–58%, improving behaviour, cognition and quality of life in both moderate and severe AD (Sadowsky et al., 2014). Rivastigmine is another commonly prescribed AChEI. It is often a treatment of preference as it also inhibits butylcholinesterase, increased in those with AD and causing an imbalance with decreased levels of AChE (Mushtag et al., 2014), and it can be administered both orally and via transdermal patch (Cacabelos, 2007; Sasaki and Horie, 2014; Farlow et al., 2015), which can be beneficial for some patients if they display more violent and restless symptoms. Galantamine is a newer drug, and is an established AChEI which is also an allosteric modulator affecting nicotinic ACh receptors, alleviating both behavioural and psychiatric symptoms of mild to moderate AD (Cacabelos, 2007; Farokhnia et al., 2014). These three drugs are medications predominantly prescribed for mild to moderate AD, effective by restoring cholinergic pathways and delaying symptom progression. The majority of drug therapies for AD focus on treating mild to moderate AD symptoms, with only a minority being targeted at severe AD. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist (Zhu et al., 2013), is the leading drug in the treatment for severe AD along with donepezil and often the two are used in conjunction (Wenk, Parsons and Danysz, 2006). Memantine works primarily by blocking excess levels of glutamate, therefore preventing glutamatergic toxicity which can be fatal for neurons in AD brains. This is achieved without affecting normal glutamatergic transmission (Wenk, Parsons and Danysz, 2006). Memantine, though not as widely used as AChEIs, does show potential neuroprotective properties such as decreasing tau protein hyperphosphorylation and consequentially inhibiting neurofibrillary tangle formation and Aβ deposition, as well as reducing the amount of damage caused to neural cells by aiding the reduction of abnormal synaptic signals (Cacabelos, 2007). Role of mitochondria in disease pathogenesis Mitochondrial dynamics in neuronal cells: Fission, fusion and function Mitochondria are constantly dividing and fusing within cells depending on environmental demands (Chan, 2006). Neurons are highly demanding cells with regards to mitochondria and require large amounts of energy. Mitochondria provide the majority of their energy to the cell through oxidative phosphorylation during the TCA cycle (Knott and Bossy-Wetzel, 2008; Bonda et al., 2010), and provide energy for many ATP-dependent neuronal processes such as synaptic transmission, vesicle release, ion channel and receptor-related processes and the reuptake and recycling of neurotransmitters (Knott and Bossy-Wetzel, 2008). Fission and fusion are the two main processes by which the mitochondria remain in synchronization with the energy demands of cells (Fig. 2). These processes also allow the spread of mitochondrial DNA (mtDNA) and metabolites during fusion processes (Santos et al., 2010), and keep the amount of defective mitochondria in the cell at a low level during fission (Bonda et al., 2010). Both processes are largely mediated by guanosine triphosphatase (GTPase) enzymes. Fission, the process of two mitochondria arising from one mitochondrial division, largely relies on two proteins: the GTPase dynamin like protein 1 (DLP-1, or DNM1L), a cytosolic protein believed to be recruited to the outer mitochondrial membrane when required; and the small protein Fis1 (Bonda et al., 2010; Santos et al., 2010). Fis1 is an outer membrane protein, and is believed to be a DLP-1 receptor and involved in DLP-1 recruitment; however, the exact mechanism is still unknown (Knott and Bossy-Wetzel, 2008; Santos et al., 2010). Fusion of mitochondria is regulated by the large GTPases mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optic atrophy protein 1 (OPA1) (Bonda et al., 2010; Santos et al., 2010). Mfn1 and Mfn2 are transmembrane proteins which span the outer mitochondrial membrane and are involved in connecting the outer membranes of nearby mitochondria to each other. However, the inner membrane must also fuse to allow the intracellular contents to merge together, which is where OPA1 is involved (Santos et al., 2010). OPA1 is an inner membrane protein which faces the intermembrane space, and requires Mfn1, but not necessarily Mfn2, to mediate the process of inner mitochondrial membrane (IMM) fusion (Santos et al., 2010). Figure 2. Open in new tabDownload slide Schematic representation of mitochondrial fission and fusion events, regulated by the proteins: Mfn 1 and 2, Opa1, Dnm1L and Fis1. (Adapted with permission from the Company of Biologists Ltd., Mandemakers, Morais and De Strooper 2007). As well as the quantity of mitochondria in a cell at any one time, the position within the cell is crucial. Within cells, mitochondria are mobile via the cytoskeleton tracks (Lacker, 2013). Axonal mitochondria motility is regulated by intracellular and mitochondrial matrix Ca2+ concentration; the number of moving mitochondria in the axon is mediated primarily through neuronal activity (Obashi and Okabe, 2013). Morphologically, abnormal fission and fusion mitochondria, elongated and short round mitochondria, respectively, also cause distribution changes within the cell. These processes, as well as the cytoskeleton, play pivotal roles in maintaining cell integrity and therefore any changes in these processes can have drastic consequences, such as the neurodegeneration observed in AD (Bonda et al., 2010). Mitochondrial dysfunction in AD Aβ in mitochondria Aβ has recently been found in mitochondria (Picone et al., 2014), accumulating in post-mortem AD brains, AD brains of living patients and the brains of transgenic AD mice (Ankarcrona, Mangialasche and Winblad, 2010). Aβ is present in mitochondria prior to amyloid plaque formation, suggesting that mitochondria are early targets for Aβ aggregates and indicating that Aβ presence in mitochondria is an early stage of AD pathogenesis (Gillardon et al., 2007; Ankarcrona, Mangialasche and Winblad, 2010). While the exact mechanism of Aβ neurotoxicity remains largely unknown, Zhang et al. (2012) identified a single proapoptotic protein, a member of the mitochondrial solute carrier family (SLC25), which interacts with APP and is associated with the characteristic neurodegeneration observed in AD. This study was conducted in vitro using yeast-two-hybrid assays identifying the SLC25A38 protein, which was assigned the name appoptosin, as the link between APP interaction and neuronal apoptosis (Zhang et al., 2012). Until recently, there was no knowledge of the function of appoptosin. Guernsey et al. (2009) provided evidence that appoptosin is responsible for transporting glycine and 5-amino-levulinic acid (δ-ALA) across the mitochondria, vital for heme synthesis. A balance of free heme and protein-bound heme is maintained via homeostasis and maintains cell integrity. Alteration of this homeostatic balance can result in excess free heme which can lead to increased reactive oxygen species (ROS) and a destabilized mitochondrial cytoskeleton (Kumar and Bandyopadhyay, 2005), ultimately resulting in faulty heme metabolism. Appoptosin regulates intrinsic caspase-dependent apoptosis via heme biosynthesis, associating appoptosin with the neuronal death seen in AD and other neurodegenerative diseases (Zhang et al., 2012). Using cultured rat hippocampal neurons it has been demonstrated that on exposure to low sub-cytotoxic levels of Aβ, severe impairment of mitochondrial transport (Rui et al., 2006), increased mtDNA levels and increased numbers of malformed mitochondria can be observed (Diana et al., 2008). Aβ binds to the Aβ-binding alcohol dehydrogenase protein in mitochondria, and by blocking this interaction both neuronal apoptosis induced by Aβ and generation of free radicals in neurons can be suppressed (Lezi and Swerdlow, 2012). These findings have also been confirmed in AD studies with human participants (Lustbader et al., 2004; Caspersen et al., 2005; Crouch et al., 2005; Devi et al., 2006). The role of Aβ mitochondria has been investigated more since these studies, and research suggests that Aβ cannot be generated locally in mitochondria (Hansson-Peterson et al., 2008), therefore it must be taken up by the organelle from elsewhere inside the cell. Using isolated rat mitochondria, it was demonstrated that Aβ is internalized by cells from an extracellular source and then imported into the mitochondria via the translocase of the outer membrane complex before accumulating in the mitochondrial cristae (Hansson-Peterson et al., 2008). Oxidative stress Oxidative stress plays a key role not only in AD pathogenesis, but also in other neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease (Dias, Junn and Mouradian, 2013). The brain is particularly vulnerable to oxidative stress due its high oxygen demand, requiring 20% of the body's oxygen despite only making up approximately 2% of the body weight (Jain, Langham and Wehrli, 2010). In a 2-year study conducted from 2010 to 2012, a correlation was observed between oxidative stress and cognitive decline in AD in those aged 63–93 years, using glutathione as a biomarker for oxidative stress (Revel et al., 2015). DNA bases are particularly vulnerable to damage caused by oxidative stress, which can trigger excitotoxic responses ultimately resulting in cell death (Feng and Wang, 2012). As part of the electron transport chain (ETC), protons are pumped across the IMM from the mitochondrial matrix, resulting in a negative membrane potential across the IMM. This causes small numbers of electrons to slowly move out of the redox enzyme complexes (Ankarcrona, Mangialasche, and Winblad, 2010) in the IMM, which are capable of forming the superoxide radical (O2−), one of the main ROS, on interaction with oxygen molecules (Picone et al., 2014). Mitochondria encompass a widespread and intense antioxidant defence mechanism in order to destroy any ROS, such as the superoxide radical, that may be formed during normal respiration. Any damage to mitochondria can result in interrupting the usual mechanisms by which ROS are destroyed, therefore increasing the number of ROS present in the organelle (Picone et al., 2014). For example, it has been found that in post-mortem AD brains there is a deficit of cytochrome c oxidase (COX), the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, in the occipital, parietal, temporal and frontal lobes as well as in the hippocampus (Mutisya, Bowling, and Beal, 1994). This dysfunction forms a cycle in which mitochondria contain more ROS due to damage, which in turn results in more damage due to an increase in the number of ROS present and so on. Excess free radicals can cause various biochemical changes observed in neurodegeneration, such as lipid peroxidation (Padurariu et al., 2013). This results in cell damage and is responsible for some of the classic pathological changes observed in neurodegenerative disease. Oxidative stress has also been found to alter Aβ levels and tau phosphorylation, the two key hallmarks of AD, via the modification of signalling pathways. Tau phosphorylation is increased via the activation of glycogen synthase kinase 3-β during high levels of oxidative stress (Lovell et al., 2004), which also increases the expression of β-secretase (Tamagno et al., 2005) and upregulates Aβ. Discovery of this link between oxidative stress in mitochondria and AD has sparked research into potential new drug targets, aimed at both oxidative stress and ROS. Potential new treatment strategies Antioxidants Antioxidants bind with free radicals to diminish the latter's highly reactive and destructive properties and decrease the damage they cause. Antioxidants have been meticulously studied with regards to reducing mitochondrial toxicity caused by oxidative stress; however, even though there has been a great amount of research conducted in this area (Kumar and Singh, 2015) it has produced debatable results due to the low permeability of the blood brain barrier to many of the antioxidants used today (Picone et al., 2014). New treatment strategies targeting this limitation have recently been tested, such as those using nanoparticles in order to deliver a more successful route for antioxidant drugs entering the central nervous system (Gomes, Martins and Sarmento, 2015). Vitamin E is a generic term for a group of naturally occurring derivatives of tocopherol and tocotrienol, and is a crucial antioxidant in protecting cellular membranes such as those found in mitochondria (Ankarcrona, Mangialasche, and Winblad 2010). α-tocopherol (Toc) (Fig. 3A) is the most studied of these with regards to AD, and has been found to significantly slow the rate of cognitive decline in those with mild to moderate (Dysken et al., 2014), albeit not being specifically targeted at mitochondria. However, in a study on aged male C57BL/6 J mice, the supplementation of one antioxidant alone had little or no effect in increasing cognitive function and it was shown that age-related cognitive dysfunction could be reversed by supplementing the mice with Toc and Coenzyme Q10 (CoQ) (Fig. 4), involved naturally in the respiratory chain in combination (Shetty et al., 2014). Figure 3. Open in new tabDownload slide Chemical structures of α-tocopherol (A), Dimebon (B) and α-lipoic acid (C). Figure 4. Open in new tabDownload slide Chemical structure of coenzyme Q10. α-lipoic acid (LA) (Fig. 3B) is itself a powerful antioxidant which has the ability to recycle other antioxidants such as vitamins C and E. LA is a naturally occurring cofactor of mitochondrial enzymes α-ketoglutarate dehydrogenase and pyruvate dehydrogenase, and has been found to increase ACh production and scavenge the toxic products of lipid peroxidation (Maczurek et al., 2008). For more than 30 years, LA has been used in Germany as a treatment for diabetic polyneuropathy (Ziegler et al., 1999). However, it was not until an elderly patient already receiving LA treatment for diabetic polyneuropathy was diagnosed with early stage AD in 1997 that clinical trials began. When this patient was diagnosed with AD, AChEIs were prescribed as standard and her course of 600 mg per day of LA was continued. Over time her AD did not worsen as rapidly as expected, and her cognitive decline was found to be surprisingly slow (Hager et al., 2001). In the subsequent clinical trial conducted by Hager et al. (2001), nine patients with probable AD were given 600 mg of LA daily, as well as either donepezil or rivastigmine. Results demonstrated that cognitive decline was slowed in these patients after the LA was prescribed in comparison to AChEIs alone. Many naturally occurring antioxidants have been tested as therapies for AD; however, most have failed to improve cognitive function. Promising new mitochondria-targeted antioxidants have been manufactured as a result of this. One of these specific antioxidants is mitoquinone mesylate, more commonly known as MitoQ (McManus, Murphy and Franklin, 2011). MitoQ accumulates in vivo and was specifically designed to protect the mitochondrial membrane from the severe damage that can be caused by lipid peroxidation and oxidative stress (Smith et al., 2012). The main antioxidant component of MitoQ is ubiquinone, identical to the active antioxidant found in CoQ, which is selectively taken up by mitochondria due to the membrane potential produced, resulting in an almost thousand fold concentration of the drug inside the mitochondrial matrix (Ng et al., 2014). The synthesis of MitoQ is carried out by covalently binding the ubiquinone component to a cation called decyltriphenylphosphonium through a long aliphatic carbon chain. The ubiquinone is then introduced to the lipid bilayer of the mitochondrial matrix where it is reduced rapidly to a product known as ubiquinol, the active antioxidant of MitoQ. This ubiquinol, once introduced, is recycled continuously via the ETC (Ng et al., 2014) (Fig. 5). Since MitoQ is found in such high concentrations within the mitochondria, it is able to neutralize free radicals before they even reach their targets and thus drastically reduces the damage that these free radicals may cause (Picone et al., 2014). Ng et al. (2014) treated transgenic Caenorhabditis elegans overexpressing human Aβ peptide, which leads to progressive paralysis in C. elegans, with MitoQ of varying concentrations in a blinded dose-response study. It was found that when administered both 1 and 5 µM MitoQ, C. elegans had significantly longer lifespans when compared to an untreated control. It was also found in a study by McManus, Murphy and Franklin (2011) that MitoQ had positive effects in a triple transgenic mouse model of AD, where MitoQ was able to prevent cognitive decline, oxidative stress, Aβ accumulation and synaptic loss in the brains of the mice. Figure 5. Open in new tabDownload slide Mechanism of MitoQ entering the cell and the mitochondria, with the recycling of MitoQ via the ETC displayed. (Reproduced from MitoQ.com, open access under the Creative Commons Attribution License CC-BY-SA 3.0.) Though this research has so far only been conducted in transgenic mouse models and C elegans, it demonstrates that mitochondria-targeted antioxidants such as MitoQ could have improved therapeutic potential when compared to natural antioxidants, and therefore could be successful treatment strategies with regards to AD and similar neurodegenerative diseases in the future. Dimebon (Latrepirdine) Latrepirdine, sold as dimebon (Fig. 3C), is a drug that has been used clinically in Russia as a non-selective antihistamine for skin allergies and allergic rhinitis since 1983 (Ankarcrona, Mangialasche and Winblad, 2010), but was withdrawn to be used for more selective treatments. The exact mechanism by which dimebon works is not yet known (Perez et al., 2012); however, in several in vitro studies, dimebon has shown to be neuroprotective against Aβ25-35 β-amyloid fragments in cerebellar granule cell cultures, designed to mimic the neurodegeneration found in the likes of AD (Bachurin et al., 2001; Lermontova et al., 2001). Dimebon has also been found to be a weak AChEI, with a half maximal inhibitory concentration (IC50) of 8–42 µM (Bachurin et al., 2001; Schaffhauser et al., 2009). It has also proved to be a weak NMDA receptor antagonist (IC50 = 10 µM) (Grigorev, Dranyi and Bachurin, 2003; Schaffhauser et al., 2009) and a weak inhibitor of voltage-gated Ca2+ channels (IC50 = 50 µM) (Lermontova et al., 2001; Schaffhauser et al., 2009). At an optimum concentration of 10 µM, dimebon has an inhibitory effect of more than 50% on a total of 18 receptors, including several serotonin receptors (Schaffhauser et al., 2009). The main component of the tau inclusions found in frontotemporal lobar degeneration, a form of dementia similar to AD characterized by severe muscle wasting, is a protein known as transactivation responsive DNA binding protein of 43 kDa (TDP-43) (Yamashita et al., 2009). This protein inclusion has also been found in a subpopulation of patients with other neurodegenerative diseases such as AD and dementia with Lewy bodies (Arai et al., 2009) as well as Huntington's disease (Schwab et al., 2008). In an in vitro study conducted on neuroblastoma SH-SY5Y cells expressing mutated TDP-43, it was found that 5 µM concentrations of dimebon over a 3-day incubation period reduced the number of TDP-43 aggregates by 45% when compared to controls (Yamashita et al., 2009), suggesting that dimebon possesses anti-oligomerization properties. Numerous trials have been conducted using dimebon as a possible therapy for AD, as was carried out by Doody et al. (2008). In this randomized, double-blind, placebo-controlled phase II trial, 183 Russian patients with mild to moderate AD were randomly assigned either 60 mg of dimebon per day or a matched placebo. Results showed a significant improvement in cognitive function and a significantly increased score on CFTs in the dimebon group compared to the placebo (Doody et al., 2008). These findings showed promise for dimebon as a potential AD therapy, sparking further study. Thus, an international double-blind phase III CONNECTION trial was conducted in 2010 using 598 participants from North America, South America and Europe. When dimebon was compared to a placebo group over a 6-month period, patients with mild to moderate AD did not show a statistically higher performance on any CFTs, and therefore dimebon did not meet CONNECTIONs co-primary (cognition and global function) or secondary efficacy end points (Pfizer Inc. and Medivation Inc., 2010). The plausibility of dimebon has been questioned by some as a treatment for AD, and it is not yet Food and Drug Administration approved as an AD treatment. Further phase III trials are ongoing in an attempt to replicate the findings of Doody et al.’s (2008) study. One randomized, double-blind, placebo-controlled phase III trial known as CONCERT enrolled approximately 1050 participants with mild to moderate AD from numerous sites across Western Europe, USA, Australia and New Zealand to participate in a 12-month study, designed to evaluate the efficacy of dimebon when added to ongoing AD treatment with donepezil (Pfizer Inc. and Medivation Inc., 2015). The results of this trial were unfortunately negative yet again, which proves detrimental for dimebon as an AD therapy, and further highlights the difficulties scientists face in finding potential treatments for diseases like AD. Conclusion Mitochondrial dysfunction is an early feature of AD pathology. Any damage to mitochondria by either Aβ or ROS can result in interrupting the usual mechanisms by which ROS are destroyed, therefore further increasing the number of ROS present in the organelle. It has been found that in post-mortem AD brains there is a deficit of COX, the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, supporting the theory that ROS are involved in the mitochondrial damage found in AD. Many antioxidants have been investigated as therapies for AD, and further studies have been carried out to find mitochondria specific antioxidants to enable a greater concentration of antioxidants to accumulate in the mitochondria, allowing a more specific method for combatting mitochondrial oxidative stress. It has been suggested that as early as 2025, prevention or effective treatment of AD may be realized (Cummings et al., 2016). Steps along this road include finding therapies that inhibit primary progenitors, reduce secondary symptoms, slow AD progression and ultimately repair damaged neurons (Feng and Wang, 2012). Further study of both generic and mitochondria specific antioxidants should be carried out to find more potential treatment strategies for Aβ induced neurotoxicity in AD and other neurodegenerative diseases. Acknowledgements Many thanks to Jane Armstrong, Mark Davies and Nicolas Haroune for helpful comments on earlier drafts of this work. Author biography Zoe L. Hawking recently graduated the University of Sunderland's BSc Biomedical Sciences degree in July 2016 with a first class honours. This review is largely unmodified from her level 5 biosciences literature review. Zoe has particular interests in both Alzheimer's disease and cancer and hopes to pursue a career in cancer biology. References Annamalai , B. , Won , J. S., Choi , S. et al. . ( 2015 ) Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation , Biochemical and Biophysical Research Communications , 29 ( 15 ), 132 – 141 . Google Scholar OpenURL Placeholder Text WorldCat Ankarcrona , M. , Mangialasche , F. and Winblad , B. ( 2010 ) Rethinking Alzheimer's disease therapy: are mitochondria the key . Journal of Alzheimer's Disease , 20 ( 2 ), 579 – 590 . Google Scholar OpenURL Placeholder Text WorldCat Arai , T. , MacKenzie , I. R., Hasegawa , M. et al. . ( 2009 ) Phosphorylated TDP-43 in Alzheimer's disease and dementia with lewy bodies , Acta Neuropathologica , 117 ( 2 ), 125 – 136 . Google Scholar Crossref Search ADS PubMed WorldCat Bachurin , S. O. , Bukatina , E., Lermontova , N. N. et al. . ( 2001 ) Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer , Annals of the New York Academy of Sciences , 939 , 425 – 435 . Google Scholar Crossref Search ADS PubMed WorldCat Biswas , J. , Goswami , P., Gupta , S. et al. . ( 2015 ) Streptozotocin induced neurotoxicity involves Alzheimer's related pathological markers: a study on N2A cells , Molecular Neurobiology . DOI:10.1007/s12035-015-9144-z. Google Scholar OpenURL Placeholder Text WorldCat Bonda , D. J. , Wang , X., Perry , G. et al. . ( 2010 ) Mitochondrial dynamics in Alzheimer's disease: opportunities for future treatment strategies , Drugs Aging , 27 ( 3 ), 181 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat Brunstromm , H. R. and Englund , E. M. ( 2009 ) Cause of death in patients with dementia disorders , European Journal of Neurology , 16 ( 4 ), 488 – 492 . Google Scholar Crossref Search ADS PubMed WorldCat Cacabelos , R . ( 2007 ) Donepezil in Alzheimer's disease: from conventional trials to pharmacogenetics , Neuropsychiatric Disease Treatment , 3 ( 3 ), 303 – 333 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Caspersen , C. , Wang , N., Yao , J. et al. . ( 2005 ) Mitochondrial abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease , The Journal of the Federation of American Societies for Experimental Biology (FASEB) , 19 ( 14 ), 2040 – 2041 . Google Scholar OpenURL Placeholder Text WorldCat Centers for Disease Control and Prevention, National Center for Health Statistics . Available at: http://wonder.cdc.gov/ucd-icd10.html [Accessed: 24 February 2015]. Chan , D. C . ( 2006 ) Mitochondrial fusion and fission in mammals , Annual Review of Cell and Developmental Biology , 22 , 79 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat Christiane , R. , Brayne , C. and Mayeux , R. ( 2011 ) Epidemiology of Alzheimer Disease , Nature Reviews Neurology , 7 ( 3 ), 137 – 152 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Crouch , P. J. , Blake , R., Duce , J. A. et al. . ( 2005 ) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta 1-42 , Journal of Neuroscience , 25 ( 3 ), 672 – 679 . Google Scholar Crossref Search ADS PubMed WorldCat Cullen , B. , O'Neill , B., Evans , J. J. et al. . ( 2007 ) A review of screening tests for cognitive impairment , Journal of Neurology, Neurosurgery and Psychiatry , 78 ( 8 ), 790 – 799 . Google Scholar Crossref Search ADS WorldCat Cummings , J. , Aisen , P. S., DuBois , B. et al. . ( 2016 ) Drug development in Alzheimer's disease: the path to 2025 , Alzheimer's Research and Therapy , 8 ( 1 ), 39 . Google Scholar Crossref Search ADS PubMed WorldCat Das , P. , Murray , B. and Belfort , G. ( 2015 ) Alzheimer's protective A2T mutation changes the conformational landscape of the Aβ1-42 monomer differently than does the A2V mutation , Biophysical Journal , 108 ( 3 ), 738 – 747 . Google Scholar Crossref Search ADS PubMed WorldCat Department of Economic and Social Affairs . ( 2001 ) World Population Ageing: 1950–2050 , USA, United Nations , New York . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Devi , L. , Prabhu , B. M., Galati , D. F. et al. . ( 2006 ) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction , Journal of Neuroscience , 26 ( 35 ), 9057 – 9068 . Google Scholar Crossref Search ADS PubMed WorldCat Diana , A. , Simic , G., Sinforiani , E. et al. . ( 2008 ) Mitochondria morphology and DNA content upon sublethal exposure to beta-amyloid (1-42) peptide , Collegium Antropologicum , 32 ( 1 ), 51 – 58 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Dias , V. , Junn , E., Mouradian , M. M. ( 2013 ) The role of oxidative stress in Parkinson's Disease , Journal of Parkinson's Disease , 3 ( 4 ), 461 – 491 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Doody , R. S. , Gavrilova , S. I., Sano , M. et al. . ( 2008 ) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , Lancet , 372 ( 9634 ), 207 – 215 . Google Scholar Crossref Search ADS PubMed WorldCat Dysken , M. W. , Sano , M., Asthana , S. et al. . ( 2014 ) Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial , The Journal of the American Medical Association , 311 ( 1 ), 33 – 44 . Google Scholar Crossref Search ADS PubMed WorldCat Fargo , K. N. , Aisen , P., Albert , M. et al. . ( 2014 ) 2014 report on the milestones for the US national plan to address Alzheimer's disease , The Journal of the Alzheimer's Association , 10 ( 5 ), 430 – 452 . Google Scholar Crossref Search ADS WorldCat Farlow , M. R. , Sadowsky , C. H., Velting , D. M. et al. . ( 2015 ) Evaluating response to high-dose 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease , CNS Neuroscience and Therapeutics , 21 ( 6 ), 513 – 519 . Google Scholar Crossref Search ADS PubMed WorldCat Farokhnia , M. , Sabet , M. S., Iranpour , N. et al. . ( 2014 ) Comparing the efficacy and safety of Crocus Sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial , Human Psychopharmacology: Clinical and Experimental , 29 , 351 – 359 . Google Scholar Crossref Search ADS WorldCat Feng , Y. and Wang , X. ( 2012 ) Antioxidant therapies for Alzheimer's disease , Oxidative Medicine and Cellular Longevity , 2012 , 1 – 17 . Google Scholar Crossref Search ADS WorldCat Gillardon , F. , Rist , W., Kussmaul , L. et al. . ( 2007 ) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition , Proteomics , 7 ( 4 ), 605 – 616 . Google Scholar Crossref Search ADS PubMed WorldCat Gomes , M. J. , Martins , S. and Sarmento , B. ( 2015 ) siRNA as a tool to improve the treatment of brain diseases: mechanism, targets and delivery , Ageing Research Reviews , 21 , 43 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Grigorev , V. V. , Dranyi , O. A. and Bachurin , S. O. ( 2003 ) Comparative study of reaction mechanisms of dimebon and memantine on AMPA- and NDMA-subtypes glutamate receptors in rat cerebral neurons , Bulletin of Experimental Biology and Medicine , 136 ( 5 ), 474 – 477 . Google Scholar Crossref Search ADS PubMed WorldCat Guernsey , D. L. , Jiang , H., Campagna , D. R. et al. . ( 2009 ) Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia , Nature Genetics , 41 ( 6 ), 651 – 653 . Google Scholar Crossref Search ADS PubMed WorldCat Guzman-Martinez , L. , Farias , G. A. and Maccioni , R. B. ( 2013 ) Tau oligomers as potential targets for Alzheimer's disease and novel drugs , Frontiers in Neurology , 4 , 167 . Google Scholar Crossref Search ADS PubMed WorldCat Hager , K. , Marahrens , A., Kenklies , M. et al. . ( 2001 ) Alpha-lipoic acid as a new treatment option for Alzheimer type dementia , Archives of Gerontology and Geriatrics , 32 ( 3 ), 275 – 282 . Google Scholar Crossref Search ADS PubMed WorldCat Hansson-Peterson , C. A. , Alikhani , H., Behbahani , H. et al. . ( 2008 ) The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae , Proceedings of the National Academy of Sciences of the United States of America , 105 ( 35 ), 13145 – 13150 . Google Scholar Crossref Search ADS PubMed WorldCat Hayden , E. Y. and Teplow , D. B. ( 2013 ) Amyloid β-protein oligomers and Alzheimer's disease , Alzheimer's Research and Therapy , 5 ( 6 ), 60 . Google Scholar Crossref Search ADS PubMed WorldCat Herholz , K . ( 2008 ) Acetylcholinesterase activity in mild cognitive impairment and Alzheimer's disease , European Journal of Nuclear Medicine and Molecular Imaging , 35 ( 1 ), 25 – 29 . Google Scholar Crossref Search ADS WorldCat Hurd , M. D. , Martorell , P., Delavande , A. et al. . ( 2013 ) Monetary costs of dementia in the United States , The New England Journal of Medicine , 368 ( 14 ), 1326 – 1334 . Google Scholar Crossref Search ADS PubMed WorldCat Jain , V. , Langham , M. C. and Wehrli , F. W. ( 2010 ) MRI estimation of global brain oxygen consumption rate , Journal of Cerebral Blood Flow and Metabolism , 30 ( 9 ), 1598 – 1607 . Google Scholar Crossref Search ADS PubMed WorldCat Knott , A. B. and Bossy-Wetzel , E. ( 2008 ) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration , Annals of the New York Academy of Sciences , 1147 , 283 – 292 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , S. and Bandyopadhyay , U. ( 2005 ) Free heme toxicity and its detoxification systems in human , Toxicology Letters , 157 ( 3 ), 175 – 188 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , A. and Singh , A. ( 2015 ) A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions , Frontiers in Pharmacology , 6 , 206 . Google Scholar Crossref Search ADS PubMed WorldCat Lacker , L. L . ( 2013 ) Determining the shape and cellular distribution of mitochondria: the integration of multiple activities , Current Opinion in Cell Biology , 25 ( 4 ), 471 – 476 . Google Scholar Crossref Search ADS PubMed WorldCat Leifer , B. P . ( 2009 ) Alzheimer's disease: seeing the signs early , Journal of the American Academy of Nurse Practitioners , 21 ( 11 ), 588 – 595 . Google Scholar Crossref Search ADS PubMed WorldCat Lermontova , N. N. , Redkozubov , A. E., Shevstova , E. F. et al. . ( 2001 ) dimebon and tacrine inhibit neurotoxic action of beta-amyloid culture and block L-Type Ca2+ channels , Bulletin of Experimental Biology and Medicine , 132 ( 5 ), 1079 – 1083 . Google Scholar Crossref Search ADS PubMed WorldCat Lezi , E. and Swerdlow , R. H. ( 2012 ) Mitochondria in neurodegeneration , Advances in Experimental Medicine and Biology , 942 , 269 – 286 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lovell , M. A. , Xiong , S., Xie , C. et al. . ( 2004 ) Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3 , Journal of Alzheimer's Disease , 6 ( 6 ), 659 – 671 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lustbader , J. W. , Cirilli , M., Lin , C. et al. . ( 2004 ) ABAD directly links abeta to mitochondrial toxicity in Alzheimer's disease , Science , 304 ( 5669 ), 448 – 452 . Google Scholar Crossref Search ADS PubMed WorldCat Maczurek , A. , Hager , K., Kenklies , M. et al. . ( 2008 ) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease , Advanced Drug Delivery Reviews , 60 ( 13-14 ), 1463 – 1470 . Google Scholar Crossref Search ADS PubMed WorldCat Mandemakers , W. , Morais , V. A. and De Strooper , B. ( 2007 ) A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases , Journal of Cell Science , 120 ( 10 ), 1707 – 1716 . Google Scholar Crossref Search ADS PubMed WorldCat Mantoani , S. P. , Chierrito , T. P., Vilela , A. F. et al. . ( 2016 ) Novel triazole-quinoline derivatives as selective dual binding site acetylcholinesterase inhibitors , Molecules , 21 ( 2 ), 193 . Google Scholar Crossref Search ADS WorldCat McManus , M. J. , Murphy , M. P. and Franklin , J. L. ( 2011 ) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathy in a transgenic mouse model of Alzheimer's disease , Journal of Neuroscience , 31 ( 44 ), 15703 – 15715 . Google Scholar Crossref Search ADS PubMed WorldCat Menting , K. W. and Claassen , J. A. H. R. ( 2014 ) β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease , Frontiers in Ageing Neuroscience , 6 ( 165 ). 10.3389/fnagi.2014.00165. Google Scholar OpenURL Placeholder Text WorldCat Mitoq.com . MitoQ. [Image] [Online] Available at: http://commons.wikimedia.org/wiki/File%3AMitoq_Accumulation.jpg [Accessed: 7 April 2015]. Mohammadi-Khanaposhtani , M. , Saeedi , M., Zafarghandi , N. S. et al. . ( 2015 ) Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation and docking study of acridone linked to 1,2,3-triazole derivatives , European Journal of Medical Chemistry , 92 , 799 – 806 . Google Scholar Crossref Search ADS WorldCat Mushtag , G. , Greig , N. H., Khan , J. A. et al. . ( 2014 ) Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus , CNS & Neurological Disorders Drug Targets , 13 ( 8 ), 1432 – 1439 . Google Scholar Crossref Search ADS PubMed WorldCat Mutisya , E. M. , Bowling , A. C. and Beal , M. F. ( 1994 ) Cortical cytochrome oxidase activity is reduced in Alzheimer's disease , Journal of Neurochemistry , 63 ( 6 ), 2179 – 2184 . Google Scholar Crossref Search ADS PubMed WorldCat Ng , L. F. , Gruber , J., Cheah , I. K. et al. . ( 2014 ) The mitochondria targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease , Free Radical Biology and Medicine , 71 , 390 – 401 . Google Scholar Crossref Search ADS PubMed WorldCat NHS UK , 2015 . Tests for Diagnosing Dementia. [Online] Available at: http://www.nhs.uk/conditions/dementia-guide/pages/dementia-diagnosis-tests.aspx [Accessed: 1 December 2015]. Obashi , K. and Okabe , S. ( 2013 ) Regulation of mitochondrial dynamics and distribution by synapse position and neuronal activity in the axon , European Journal of Neuroscience , 38 ( 3 ), 2350 – 2363 . Google Scholar Crossref Search ADS PubMed WorldCat Obregon , D. , Hou , H., Deng , J. et al. . ( 2012 ) sAPP-α modulates β-secretase activity and amyloid-β generation , Nature Communications , 10 ( 3 ), 777 . Google Scholar Crossref Search ADS WorldCat O'Brien , R. J. and Wong , P. C. ( 2011 ) Amyloid precursor protein processing and Alzheimer's disease , Annual Review of Neuroscience , 34 , 185 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat Obulesu , M. and Lakshmi , M. J. ( 2014 ) Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues , Neurochemical Research , 39 ( 12 ), 2301 – 2312 . Google Scholar Crossref Search ADS PubMed WorldCat Padurariu , M. , Ciobica , A., Lefter , R. et al. . ( 2013 ) The oxidative , Stress Hypothesis in Alzheimer's Disease , 25 ( 4 ), 401 – 409 . Google Scholar OpenURL Placeholder Text WorldCat Perez , S. E. , Nadeem , M., Sadleir , K. R. et al. . ( 2012 ) Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice , International Journal of Physiology, Pathophysiology and Pharmacology , 4 ( 3 ), 115 – 127 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Picone , P. , Nuzzo , D., Caruana , L. et al. . ( 2014 ) Mitochondrial dysfunction: different routes to Alzheimer's disease therapy , Oxidative Medicine and Cellular Longevity , 2014 , 1 – 11 . Google Scholar Crossref Search ADS WorldCat Pfizer Press Inc. and Medivation Inc . ( 2010 ). Pfizer and medivation announce results from two phase 3 studies in Dimebon (Latrepirdine*) Alzheimer's disease clinical development program. [Online] Available at: http://investors.medivation.com/releasedetail.cfm?releaseID=448818 [Accessed: 10 April 2015]. Pfizer Press Inc. and Medivation Inc . ( 2015 ). Pfizer and medivation initiate phase 3 trial of dimebon added to donepezil in patients with Alzheimer's disease. [Online] Available at: http://www.prnewswire.com/news-releases/pfizer-and-medivation-initiate-phase-3-trial-of-dimebon-added-to-donepezil-in-patients-with-alzheimers-disease-61820322.html [Accessed: 19 April 2015]. Qiu , C. , Kivipelto , M. and von Strauss , E. ( 2009 ) Epidemiology of Alzheimer's disease: occurrence, determinants and strategies toward intervention , Dialogues in Clinical Neuroscience , 11 ( 2 ), 111 – 128 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Revel , F. , Gilbert , T., Roche , S. et al. . ( 2015 ) Influence of oxidative stress on cognitive decline , Journal of Alzheimer's Disease , 45 ( 2 ), 553 – 560 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Rui , Y. , Tiwari , P., Xie , Z. et al. . ( 2006 ) Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons , Journal of Neuroscience , 26 ( 41 ), 10480 – 10487 . Google Scholar Crossref Search ADS PubMed WorldCat Sadowsky , C. H. , Micca , J. L., Grossberg , G. T. et al. . ( 2014 ) Rivastigmine from capsule to patch: therapeutci advances in the management of Alzheimer's disease and Parkinson's disease dementia , The Primary Care Companion for CNS Disorders , 16 ( 5 ), 1654 – 1662 . Google Scholar OpenURL Placeholder Text WorldCat Santos , R. X. , Correia , S. C., Wang , X. et al. . ( 2010 ) a synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease , Journal of Alzheimer's Disease: JAD , 20 ( 2 ), 401 – 412 . Google Scholar OpenURL Placeholder Text WorldCat Sasaki , S. and Horie , Y. ( 2014 ) The effects of an uninterrupted switch from donepezil to galantamine without dose titration on behavioral and psychological symptoms of dementia in Alzheimer's disease , Dementia and Geriatric Cognitive Disorders Extra , 4 ( 2 ), 131 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat Schaffhauser , H. , Mathiasen , J. R., DiCamillo , A. et al. . ( 2009 ) Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities , Biochemical Pharmacology , 78 ( 8 ), 1035 – 1042 . Google Scholar Crossref Search ADS PubMed WorldCat Schwab , C. , Arai , T., Hasegawa , M. et al. . ( 2008 ) Colocalization of transactivation-responsive DNA binding protein 43 and huntingtin in inclusions of huntington disease , Journal of Neuropathology and Experimental Neurology , 67 ( 12 ), 1159 – 1165 . Google Scholar Crossref Search ADS PubMed WorldCat Shetty , R. A. , Ikonne , U. S., Forster , M. J. and Sumien , N. ( 2014 ) Coenzyme Q10 and α-tocopherol reversed age-associated functional impairments in mice , Experimental Gerontology , 2014 , 208 – 218 . Google Scholar Crossref Search ADS WorldCat Smith , R. A. , Hartley , R. C., Cocheme , H. M. et al. . ( 2012 ) Mitochondrial pharmacology , Trends in Pharmacological Sciences , 33 , 341 – 352 . Google Scholar Crossref Search ADS PubMed WorldCat Sperling , R. A. , Aisen , P. S., Beckett , L. A. et al. . ( 2011 ) Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , Alzheimer's & Dementia , 7 ( 3 ), 280 – 292 . Google Scholar Crossref Search ADS WorldCat Tamagno , E. , Parola , M., Bardini , P. et al. . ( 2005 ) β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress activated protein kinases pathways , Journal of Neurochemistry , 92 ( 3 ), 628 – 636 . Google Scholar Crossref Search ADS PubMed WorldCat Walsh , D. M. and Selkoe , D. J. ( 2007 ) Aβ oligomers: a decade of discovery , Journal of Neurochemistry , 101 ( 5 ), 1172 – 1184 . Google Scholar Crossref Search ADS PubMed WorldCat Wang , X. , Su , B., Zheng , L. et al. . ( 2009 ) The role of mitochondrial dynamics in the pathogenesis of Alzheimer's disease , Journal of Neurochemistry , 109 , 153 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat Wenk , G. L. , Parsons , C. G. and Danysz , W. ( 2006 ) Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine , Behavioural Pharmacology , 17 , 411 – 424 . Google Scholar Crossref Search ADS PubMed WorldCat Yamashita , M. , Nonaka , T., Arai , T. et al. . ( 2009 ) Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models , FEBS Letters , 583 ( 14 ), 2419 – 2424 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , H. , Zhang. , Y., Chen , Y. et al. . ( 2012 ) Appoptosin is a novel proapoptotic protein and mediates cell death in neurodegeneration , The Journal of Neuroscience , 32 ( 44 ), 15565 – 15576 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , Y. , Thompson , R., Zhang , H. et al. . ( 2011 ) APP processing in Alzheimer's disease , Molecular Brain, 4 (3) . DOI:10.1186/1756-6606-4-3. Google Scholar OpenURL Placeholder Text WorldCat Zhou , A. , Wu , H., Pan , J. et al. . ( 2015 ) Synthesis and evolution of paeonol derivatives as potential multifunctional agents for the treatments of Alzheimer's disease , Molecules , 20 ( 1 ), 1304 – 1318 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu , M. , Xiao , S., Li , G. et al. . ( 2013 ) Effectiveness and safety of generic memantine hydrochloride manufactured in china in the treatment of moderate to severe Alzheimer's disease: a multicenter, double-blind randomized controlled trial , Shanghai Archives of Psychiatry , 25 ( 4 ), 244 – 253 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Ziegler , D. , Reljanovic , M., Mehnert , H. et al. . ( 1999 ) Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials , Experimental and Clinical Endocrinology & Diabetes , 107 ( 7 ), 421 – 430 . Google Scholar Crossref Search ADS WorldCat Author notes † Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author 2016. Published by Oxford University Press.

Loading next page...
 
/lp/oxford-university-press/alzheimer-s-disease-the-role-of-mitochondrial-dysfunction-and-1pT688dHey

References (99)

Publisher
Oxford University Press
Copyright
Copyright © 2022 Oxford University Press
eISSN
1754-7431
DOI
10.1093/biohorizons/hzw014
Publisher site
See Article on Publisher Site

Abstract

Abstract Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD. As these drugs simply delay the onset of symptoms, the development of new therapies is key. As neurons are highly energy-demanding cells, they rely heavily on the functions of mitochondria, and any dysfunction affecting respiratory processes can be devastating and lead to the neuronal death characteristic of AD. Dysfunction in fission and fusion processes of mitochondria have been observed in early AD and are heavily involved in AD pathogenesis. Beta-amyloid (Aβ) is a neurotoxic protein formed in the AD brain as a result of inappropriate secretase activity and is one of the major hallmarks of the disease. Aβ has recently been discovered in the membranes of mitochondria, disabling many basic respiratory functions. Ongoing research is largely targeted at protecting mitochondria from damage caused by factors such as Aβ and oxidative stress. Antioxidants have been meticulously studied, and several generic antioxidants such as α-tocopherol have been found to significantly slow the rate of cognitive decline in both mild to moderate and severe AD. MitoQ is a mitochondria specific antioxidant which is able to enter mitochondria in an almost thousand fold greater concentration than is achieved by generic antioxidants. This enables protection against potentially devastating factors for mitochondria, such as lipid peroxidation, oxidative stress and Aβ neurotoxicity. This review further discusses mitochondrial therapies as well as other new treatments for AD. β-amyloid, acetylcholine, mitochondria, MitoQ, antioxidants, reactive oxygen species (ROS) Introduction Alzheimer's disease (AD) is the leading cause of dementia worldwide. Dementia patients totalled 24.2 million in 2005 and 4.2 million cases arose each year from 2005 to 2011, with 70% of these cases being a result of AD (Christiane, Brayne and Mayeux, 2011). AD predominantly affects more women than men, and the number of people dying as a result of the disease increased by 55.7 people per hundred thousand in the USA from 2000 to 2010 (Centers for Disease Control and Prevention, NCHS, 2008). Frequently, the cause of death of AD sufferers is a secondary condition such as pneumonia or ischaemic heart disease which can be exacerbated by many of the symptoms of AD (Brunnstrom and Englund, 2009). The number of people developing AD is expected to triple by the year 2050 (Mohammadi-Khanaposhtani et al., 2015), when it is estimated that 4.1% of the population will be over 80 years of age (Department of Economic and Social Affairs, 2001). In developed countries, 1 in 10 people over the age of 65 are affected by dementia of some form, with the frequency of AD almost doubling within this specific population every 5 years (Qiu, Kivipelto and von Strauss, 2009). Worldwide, the cost of medical care for dementia sufferers totals approximately 604 billion US$ (Fargo et al., 2014), with the annual cost of AD per patient ranging from between US$42 000 and US$56 000 in the USA (Hurd et al., 2013). Clearly AD is both widespread and costly. AD is a progressive, age-associated neurodegenerative disease which is characterized by neuronal loss and accompanying cognitive impairment (Walsh and Selkoe, 2007; Bonda et al., 2010), with symptoms ranging from ‘preclinical’ (Sperling et al., 2011) to severe. Early symptoms of AD may first be mistaken by friends and family members as normal signs of ageing, however as the disease progresses symptoms worsen rapidly, though the rate at which this happens differs between individuals. Later stages of the disease result in the sufferer being unable to perform everyday tasks such as carrying out basic hygiene routines, or being able to bathe or eat independently (Leifer, 2009). AD commonly goes undiagnosed until it reaches these more debilitating stages. The mini mental state examination is used to assess the level of cognitive impairment that a dementia patient may be experiencing via a series of exercises, such as memorizing a list of objects or correctly answering time-orientation questions (NHS-UK, 2015). Further tests such as blood tests and MRI or CT scans may then be taken, characteristically showing diminished brain tissue as a result of neuronal loss, forming a definitive diagnosis (Cullen et al., 2007). The most popular theory regarding AD onset is the role of Aβ, a fundamental component of extracellular plaques that accumulate in the brains of AD sufferers via amyloidogenesis (Picone et al., 2014). This process is known to be a leading cause of the neuronal loss that can be observed in AD and is a recognized hallmark of the disease (Bonda et al., 2010; Das, Murray and Belfort, 2015). Similarly, microtubule associated tau proteins become hyperphosphorylated and form neurofibrillary tangles which is also recognized as a hallmark of the disease (Bonda et al., 2010; Annamalai et al., 2015). It is thought that as well as these known hallmarks, mitochondrial malfunctions play a distinct role in AD pathogenesis (Obulesu and Lakshmi, 2014). The processes of fission and fusion are vital in mitochondrial dynamics in order to maintain a balance of the morphology, number, distribution, and function of these organelles within cells (Wang et al., 2009). When these processes become unbalanced, mitochondria are unable to adequately carry out their functions making them vulnerable to consequences such as oxidative stress which can lead to the neurodegeneration typically seen in AD (Bonda et al., 2010). This review will outline the pathophysiology of AD and the current medications used, and primarily focus on newer treatment strategies such as therapies targeted at mitochondrial dysfunction in neurons. It will explain the possible benefits of these newer treatment techniques, currently undergoing clinical testing, and demonstrate the difficulties associated with finding successful AD therapies. Pathophysiology of AD and currently available medications Pathophysiology of AD Amyloid precursor protein (APP) is a type I transmembrane protein which is synthesized in the endoplasmic reticulum (O'Brien and Wong, 2011) and found in the neuronal cell membrane, with a large extracellular N-terminus and a shorter intracellular C-terminus. APP must be cleaved into smaller fragments by proteases in order to be functional. In healthy brains, a protease known as α-secretase carries out the first cleavage followed by a secondary cleavage from γ-secretase, giving rise to the nonamyloidgenic pathway. This forms the alpha C-terminal fragment and also causes APP to release its extracellular domain, known as APPsα (Obregon et al., 2012), which are thought to be beneficial to neurons (Zhang et al., 2011). In AD, APP is formed incorrectly due to an excess of β-secretase. When APP is first cleaved by β-secretase as opposed to α-secretase, C-terminal fragment β-CTF along with the soluble N-terminal fragment APPsβ are generated. γ-secretase further processes the β-CTF fragment, forming Aβ fragments of varying lengths; Aβ40 and Aβ42 being the primary toxic species found in AD brains (Obregon et al., 2012). This is known as the amyloidgenic pathway (Obregon et al., 2012; Picone et al., 2014) (Fig. 1). As more Aβ40 and Aβ42 are released, the Aβ oligomers increase in size and become insoluble and increasingly toxic to neurons, forming the aforementioned Aβ plaques (Hayden and Teplow, 2013). Figure 1. Open in new tabDownload slide Nonamyloidgenic and amyloidgenic pathways originate from different APP processing. The nonamyloidgenic pathway sees cleavage of α-secretase produce the healthy APPsα fragment, with further cleavage of γ-secretase giving rise to no Aβ generation. In AD, β-secretase forms the initial cleavage producing the APPsβ fragment, with γ-secretase combining to produce Aβ plaques in the amyloidgenic pathway. (Reproduced from Menting and Claassen 2014, open access under the Creative Commons Attribution License CC-BY.) In the brains of healthy individuals, tau stabilizes components critical to the internal transport system of neurons. Tau attaches to microtubules along the length of the neuron, allowing nutrients and other metabolic substances to be transported throughout the cell (Guzman-Martinez, Farias and Maccioni, 2013). In AD brains, tau is modified, causing it to separate from the microtubules therefore resulting in their degradation. Intracellular tangles formed by tau protein hyperphosphorylation disable the transport system and inactivate the neuron. Neurons are unable to regenerate, therefore as these processes continue neurons begin to disconnect from each other and eventually die, leading to memory loss, cognitive decline and other symptoms associated with AD as the brain tissue gradually shrinks and loses function. In AD patients, cholinergic pathways become compromised in the basal forebrain and cerebral cortex (Herholz, 2008), primarily due to an excess amount of acetylcholinesterase (AChE), leading to a decrease in acetylcholine (ACh) levels (Zhou et al., 2015). These cholinergic deficits are thought by many to be a major factor in AD (Herholz, 2008; Biswas et al., 2015; Zhou et al., 2015). Evidence suggests that AChE can also interact with Aβ and increase the number and toxicity of Aβ plaques via interaction with AChEs peripheral binding site (Mantoani et al., 2016). Currently available medications to target neurotransmitters ACh has been found to be greatly reduced in sufferers of AD compared to healthy controls (Ankarcrona, Mangialasche and Winblad, 2010; Zhou et al., 2015). Drugs currently available on the UK National Health Service work primarily by reducing AChE levels and therefore restoring levels of cholinergic transmission in the brain. Drugs can also be prescribed which target glutamatergic transmission, as both glutamatergic and cholinergic transmission are impaired in the brains of AD sufferers (Cacabelos, 2007). There are four main drugs currently in use for the relief of symptoms of AD: donepezil, rivastigmine, galantamine and, usually only prescribed for severe AD, memantine. Donepezil is the most commonly prescribed drug for AD in more than 50 countries. It is a highly selective AChE inhibitor (AChEI) with a response rate of 40–58%, improving behaviour, cognition and quality of life in both moderate and severe AD (Sadowsky et al., 2014). Rivastigmine is another commonly prescribed AChEI. It is often a treatment of preference as it also inhibits butylcholinesterase, increased in those with AD and causing an imbalance with decreased levels of AChE (Mushtag et al., 2014), and it can be administered both orally and via transdermal patch (Cacabelos, 2007; Sasaki and Horie, 2014; Farlow et al., 2015), which can be beneficial for some patients if they display more violent and restless symptoms. Galantamine is a newer drug, and is an established AChEI which is also an allosteric modulator affecting nicotinic ACh receptors, alleviating both behavioural and psychiatric symptoms of mild to moderate AD (Cacabelos, 2007; Farokhnia et al., 2014). These three drugs are medications predominantly prescribed for mild to moderate AD, effective by restoring cholinergic pathways and delaying symptom progression. The majority of drug therapies for AD focus on treating mild to moderate AD symptoms, with only a minority being targeted at severe AD. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist (Zhu et al., 2013), is the leading drug in the treatment for severe AD along with donepezil and often the two are used in conjunction (Wenk, Parsons and Danysz, 2006). Memantine works primarily by blocking excess levels of glutamate, therefore preventing glutamatergic toxicity which can be fatal for neurons in AD brains. This is achieved without affecting normal glutamatergic transmission (Wenk, Parsons and Danysz, 2006). Memantine, though not as widely used as AChEIs, does show potential neuroprotective properties such as decreasing tau protein hyperphosphorylation and consequentially inhibiting neurofibrillary tangle formation and Aβ deposition, as well as reducing the amount of damage caused to neural cells by aiding the reduction of abnormal synaptic signals (Cacabelos, 2007). Role of mitochondria in disease pathogenesis Mitochondrial dynamics in neuronal cells: Fission, fusion and function Mitochondria are constantly dividing and fusing within cells depending on environmental demands (Chan, 2006). Neurons are highly demanding cells with regards to mitochondria and require large amounts of energy. Mitochondria provide the majority of their energy to the cell through oxidative phosphorylation during the TCA cycle (Knott and Bossy-Wetzel, 2008; Bonda et al., 2010), and provide energy for many ATP-dependent neuronal processes such as synaptic transmission, vesicle release, ion channel and receptor-related processes and the reuptake and recycling of neurotransmitters (Knott and Bossy-Wetzel, 2008). Fission and fusion are the two main processes by which the mitochondria remain in synchronization with the energy demands of cells (Fig. 2). These processes also allow the spread of mitochondrial DNA (mtDNA) and metabolites during fusion processes (Santos et al., 2010), and keep the amount of defective mitochondria in the cell at a low level during fission (Bonda et al., 2010). Both processes are largely mediated by guanosine triphosphatase (GTPase) enzymes. Fission, the process of two mitochondria arising from one mitochondrial division, largely relies on two proteins: the GTPase dynamin like protein 1 (DLP-1, or DNM1L), a cytosolic protein believed to be recruited to the outer mitochondrial membrane when required; and the small protein Fis1 (Bonda et al., 2010; Santos et al., 2010). Fis1 is an outer membrane protein, and is believed to be a DLP-1 receptor and involved in DLP-1 recruitment; however, the exact mechanism is still unknown (Knott and Bossy-Wetzel, 2008; Santos et al., 2010). Fusion of mitochondria is regulated by the large GTPases mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optic atrophy protein 1 (OPA1) (Bonda et al., 2010; Santos et al., 2010). Mfn1 and Mfn2 are transmembrane proteins which span the outer mitochondrial membrane and are involved in connecting the outer membranes of nearby mitochondria to each other. However, the inner membrane must also fuse to allow the intracellular contents to merge together, which is where OPA1 is involved (Santos et al., 2010). OPA1 is an inner membrane protein which faces the intermembrane space, and requires Mfn1, but not necessarily Mfn2, to mediate the process of inner mitochondrial membrane (IMM) fusion (Santos et al., 2010). Figure 2. Open in new tabDownload slide Schematic representation of mitochondrial fission and fusion events, regulated by the proteins: Mfn 1 and 2, Opa1, Dnm1L and Fis1. (Adapted with permission from the Company of Biologists Ltd., Mandemakers, Morais and De Strooper 2007). As well as the quantity of mitochondria in a cell at any one time, the position within the cell is crucial. Within cells, mitochondria are mobile via the cytoskeleton tracks (Lacker, 2013). Axonal mitochondria motility is regulated by intracellular and mitochondrial matrix Ca2+ concentration; the number of moving mitochondria in the axon is mediated primarily through neuronal activity (Obashi and Okabe, 2013). Morphologically, abnormal fission and fusion mitochondria, elongated and short round mitochondria, respectively, also cause distribution changes within the cell. These processes, as well as the cytoskeleton, play pivotal roles in maintaining cell integrity and therefore any changes in these processes can have drastic consequences, such as the neurodegeneration observed in AD (Bonda et al., 2010). Mitochondrial dysfunction in AD Aβ in mitochondria Aβ has recently been found in mitochondria (Picone et al., 2014), accumulating in post-mortem AD brains, AD brains of living patients and the brains of transgenic AD mice (Ankarcrona, Mangialasche and Winblad, 2010). Aβ is present in mitochondria prior to amyloid plaque formation, suggesting that mitochondria are early targets for Aβ aggregates and indicating that Aβ presence in mitochondria is an early stage of AD pathogenesis (Gillardon et al., 2007; Ankarcrona, Mangialasche and Winblad, 2010). While the exact mechanism of Aβ neurotoxicity remains largely unknown, Zhang et al. (2012) identified a single proapoptotic protein, a member of the mitochondrial solute carrier family (SLC25), which interacts with APP and is associated with the characteristic neurodegeneration observed in AD. This study was conducted in vitro using yeast-two-hybrid assays identifying the SLC25A38 protein, which was assigned the name appoptosin, as the link between APP interaction and neuronal apoptosis (Zhang et al., 2012). Until recently, there was no knowledge of the function of appoptosin. Guernsey et al. (2009) provided evidence that appoptosin is responsible for transporting glycine and 5-amino-levulinic acid (δ-ALA) across the mitochondria, vital for heme synthesis. A balance of free heme and protein-bound heme is maintained via homeostasis and maintains cell integrity. Alteration of this homeostatic balance can result in excess free heme which can lead to increased reactive oxygen species (ROS) and a destabilized mitochondrial cytoskeleton (Kumar and Bandyopadhyay, 2005), ultimately resulting in faulty heme metabolism. Appoptosin regulates intrinsic caspase-dependent apoptosis via heme biosynthesis, associating appoptosin with the neuronal death seen in AD and other neurodegenerative diseases (Zhang et al., 2012). Using cultured rat hippocampal neurons it has been demonstrated that on exposure to low sub-cytotoxic levels of Aβ, severe impairment of mitochondrial transport (Rui et al., 2006), increased mtDNA levels and increased numbers of malformed mitochondria can be observed (Diana et al., 2008). Aβ binds to the Aβ-binding alcohol dehydrogenase protein in mitochondria, and by blocking this interaction both neuronal apoptosis induced by Aβ and generation of free radicals in neurons can be suppressed (Lezi and Swerdlow, 2012). These findings have also been confirmed in AD studies with human participants (Lustbader et al., 2004; Caspersen et al., 2005; Crouch et al., 2005; Devi et al., 2006). The role of Aβ mitochondria has been investigated more since these studies, and research suggests that Aβ cannot be generated locally in mitochondria (Hansson-Peterson et al., 2008), therefore it must be taken up by the organelle from elsewhere inside the cell. Using isolated rat mitochondria, it was demonstrated that Aβ is internalized by cells from an extracellular source and then imported into the mitochondria via the translocase of the outer membrane complex before accumulating in the mitochondrial cristae (Hansson-Peterson et al., 2008). Oxidative stress Oxidative stress plays a key role not only in AD pathogenesis, but also in other neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease (Dias, Junn and Mouradian, 2013). The brain is particularly vulnerable to oxidative stress due its high oxygen demand, requiring 20% of the body's oxygen despite only making up approximately 2% of the body weight (Jain, Langham and Wehrli, 2010). In a 2-year study conducted from 2010 to 2012, a correlation was observed between oxidative stress and cognitive decline in AD in those aged 63–93 years, using glutathione as a biomarker for oxidative stress (Revel et al., 2015). DNA bases are particularly vulnerable to damage caused by oxidative stress, which can trigger excitotoxic responses ultimately resulting in cell death (Feng and Wang, 2012). As part of the electron transport chain (ETC), protons are pumped across the IMM from the mitochondrial matrix, resulting in a negative membrane potential across the IMM. This causes small numbers of electrons to slowly move out of the redox enzyme complexes (Ankarcrona, Mangialasche, and Winblad, 2010) in the IMM, which are capable of forming the superoxide radical (O2−), one of the main ROS, on interaction with oxygen molecules (Picone et al., 2014). Mitochondria encompass a widespread and intense antioxidant defence mechanism in order to destroy any ROS, such as the superoxide radical, that may be formed during normal respiration. Any damage to mitochondria can result in interrupting the usual mechanisms by which ROS are destroyed, therefore increasing the number of ROS present in the organelle (Picone et al., 2014). For example, it has been found that in post-mortem AD brains there is a deficit of cytochrome c oxidase (COX), the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, in the occipital, parietal, temporal and frontal lobes as well as in the hippocampus (Mutisya, Bowling, and Beal, 1994). This dysfunction forms a cycle in which mitochondria contain more ROS due to damage, which in turn results in more damage due to an increase in the number of ROS present and so on. Excess free radicals can cause various biochemical changes observed in neurodegeneration, such as lipid peroxidation (Padurariu et al., 2013). This results in cell damage and is responsible for some of the classic pathological changes observed in neurodegenerative disease. Oxidative stress has also been found to alter Aβ levels and tau phosphorylation, the two key hallmarks of AD, via the modification of signalling pathways. Tau phosphorylation is increased via the activation of glycogen synthase kinase 3-β during high levels of oxidative stress (Lovell et al., 2004), which also increases the expression of β-secretase (Tamagno et al., 2005) and upregulates Aβ. Discovery of this link between oxidative stress in mitochondria and AD has sparked research into potential new drug targets, aimed at both oxidative stress and ROS. Potential new treatment strategies Antioxidants Antioxidants bind with free radicals to diminish the latter's highly reactive and destructive properties and decrease the damage they cause. Antioxidants have been meticulously studied with regards to reducing mitochondrial toxicity caused by oxidative stress; however, even though there has been a great amount of research conducted in this area (Kumar and Singh, 2015) it has produced debatable results due to the low permeability of the blood brain barrier to many of the antioxidants used today (Picone et al., 2014). New treatment strategies targeting this limitation have recently been tested, such as those using nanoparticles in order to deliver a more successful route for antioxidant drugs entering the central nervous system (Gomes, Martins and Sarmento, 2015). Vitamin E is a generic term for a group of naturally occurring derivatives of tocopherol and tocotrienol, and is a crucial antioxidant in protecting cellular membranes such as those found in mitochondria (Ankarcrona, Mangialasche, and Winblad 2010). α-tocopherol (Toc) (Fig. 3A) is the most studied of these with regards to AD, and has been found to significantly slow the rate of cognitive decline in those with mild to moderate (Dysken et al., 2014), albeit not being specifically targeted at mitochondria. However, in a study on aged male C57BL/6 J mice, the supplementation of one antioxidant alone had little or no effect in increasing cognitive function and it was shown that age-related cognitive dysfunction could be reversed by supplementing the mice with Toc and Coenzyme Q10 (CoQ) (Fig. 4), involved naturally in the respiratory chain in combination (Shetty et al., 2014). Figure 3. Open in new tabDownload slide Chemical structures of α-tocopherol (A), Dimebon (B) and α-lipoic acid (C). Figure 4. Open in new tabDownload slide Chemical structure of coenzyme Q10. α-lipoic acid (LA) (Fig. 3B) is itself a powerful antioxidant which has the ability to recycle other antioxidants such as vitamins C and E. LA is a naturally occurring cofactor of mitochondrial enzymes α-ketoglutarate dehydrogenase and pyruvate dehydrogenase, and has been found to increase ACh production and scavenge the toxic products of lipid peroxidation (Maczurek et al., 2008). For more than 30 years, LA has been used in Germany as a treatment for diabetic polyneuropathy (Ziegler et al., 1999). However, it was not until an elderly patient already receiving LA treatment for diabetic polyneuropathy was diagnosed with early stage AD in 1997 that clinical trials began. When this patient was diagnosed with AD, AChEIs were prescribed as standard and her course of 600 mg per day of LA was continued. Over time her AD did not worsen as rapidly as expected, and her cognitive decline was found to be surprisingly slow (Hager et al., 2001). In the subsequent clinical trial conducted by Hager et al. (2001), nine patients with probable AD were given 600 mg of LA daily, as well as either donepezil or rivastigmine. Results demonstrated that cognitive decline was slowed in these patients after the LA was prescribed in comparison to AChEIs alone. Many naturally occurring antioxidants have been tested as therapies for AD; however, most have failed to improve cognitive function. Promising new mitochondria-targeted antioxidants have been manufactured as a result of this. One of these specific antioxidants is mitoquinone mesylate, more commonly known as MitoQ (McManus, Murphy and Franklin, 2011). MitoQ accumulates in vivo and was specifically designed to protect the mitochondrial membrane from the severe damage that can be caused by lipid peroxidation and oxidative stress (Smith et al., 2012). The main antioxidant component of MitoQ is ubiquinone, identical to the active antioxidant found in CoQ, which is selectively taken up by mitochondria due to the membrane potential produced, resulting in an almost thousand fold concentration of the drug inside the mitochondrial matrix (Ng et al., 2014). The synthesis of MitoQ is carried out by covalently binding the ubiquinone component to a cation called decyltriphenylphosphonium through a long aliphatic carbon chain. The ubiquinone is then introduced to the lipid bilayer of the mitochondrial matrix where it is reduced rapidly to a product known as ubiquinol, the active antioxidant of MitoQ. This ubiquinol, once introduced, is recycled continuously via the ETC (Ng et al., 2014) (Fig. 5). Since MitoQ is found in such high concentrations within the mitochondria, it is able to neutralize free radicals before they even reach their targets and thus drastically reduces the damage that these free radicals may cause (Picone et al., 2014). Ng et al. (2014) treated transgenic Caenorhabditis elegans overexpressing human Aβ peptide, which leads to progressive paralysis in C. elegans, with MitoQ of varying concentrations in a blinded dose-response study. It was found that when administered both 1 and 5 µM MitoQ, C. elegans had significantly longer lifespans when compared to an untreated control. It was also found in a study by McManus, Murphy and Franklin (2011) that MitoQ had positive effects in a triple transgenic mouse model of AD, where MitoQ was able to prevent cognitive decline, oxidative stress, Aβ accumulation and synaptic loss in the brains of the mice. Figure 5. Open in new tabDownload slide Mechanism of MitoQ entering the cell and the mitochondria, with the recycling of MitoQ via the ETC displayed. (Reproduced from MitoQ.com, open access under the Creative Commons Attribution License CC-BY-SA 3.0.) Though this research has so far only been conducted in transgenic mouse models and C elegans, it demonstrates that mitochondria-targeted antioxidants such as MitoQ could have improved therapeutic potential when compared to natural antioxidants, and therefore could be successful treatment strategies with regards to AD and similar neurodegenerative diseases in the future. Dimebon (Latrepirdine) Latrepirdine, sold as dimebon (Fig. 3C), is a drug that has been used clinically in Russia as a non-selective antihistamine for skin allergies and allergic rhinitis since 1983 (Ankarcrona, Mangialasche and Winblad, 2010), but was withdrawn to be used for more selective treatments. The exact mechanism by which dimebon works is not yet known (Perez et al., 2012); however, in several in vitro studies, dimebon has shown to be neuroprotective against Aβ25-35 β-amyloid fragments in cerebellar granule cell cultures, designed to mimic the neurodegeneration found in the likes of AD (Bachurin et al., 2001; Lermontova et al., 2001). Dimebon has also been found to be a weak AChEI, with a half maximal inhibitory concentration (IC50) of 8–42 µM (Bachurin et al., 2001; Schaffhauser et al., 2009). It has also proved to be a weak NMDA receptor antagonist (IC50 = 10 µM) (Grigorev, Dranyi and Bachurin, 2003; Schaffhauser et al., 2009) and a weak inhibitor of voltage-gated Ca2+ channels (IC50 = 50 µM) (Lermontova et al., 2001; Schaffhauser et al., 2009). At an optimum concentration of 10 µM, dimebon has an inhibitory effect of more than 50% on a total of 18 receptors, including several serotonin receptors (Schaffhauser et al., 2009). The main component of the tau inclusions found in frontotemporal lobar degeneration, a form of dementia similar to AD characterized by severe muscle wasting, is a protein known as transactivation responsive DNA binding protein of 43 kDa (TDP-43) (Yamashita et al., 2009). This protein inclusion has also been found in a subpopulation of patients with other neurodegenerative diseases such as AD and dementia with Lewy bodies (Arai et al., 2009) as well as Huntington's disease (Schwab et al., 2008). In an in vitro study conducted on neuroblastoma SH-SY5Y cells expressing mutated TDP-43, it was found that 5 µM concentrations of dimebon over a 3-day incubation period reduced the number of TDP-43 aggregates by 45% when compared to controls (Yamashita et al., 2009), suggesting that dimebon possesses anti-oligomerization properties. Numerous trials have been conducted using dimebon as a possible therapy for AD, as was carried out by Doody et al. (2008). In this randomized, double-blind, placebo-controlled phase II trial, 183 Russian patients with mild to moderate AD were randomly assigned either 60 mg of dimebon per day or a matched placebo. Results showed a significant improvement in cognitive function and a significantly increased score on CFTs in the dimebon group compared to the placebo (Doody et al., 2008). These findings showed promise for dimebon as a potential AD therapy, sparking further study. Thus, an international double-blind phase III CONNECTION trial was conducted in 2010 using 598 participants from North America, South America and Europe. When dimebon was compared to a placebo group over a 6-month period, patients with mild to moderate AD did not show a statistically higher performance on any CFTs, and therefore dimebon did not meet CONNECTIONs co-primary (cognition and global function) or secondary efficacy end points (Pfizer Inc. and Medivation Inc., 2010). The plausibility of dimebon has been questioned by some as a treatment for AD, and it is not yet Food and Drug Administration approved as an AD treatment. Further phase III trials are ongoing in an attempt to replicate the findings of Doody et al.’s (2008) study. One randomized, double-blind, placebo-controlled phase III trial known as CONCERT enrolled approximately 1050 participants with mild to moderate AD from numerous sites across Western Europe, USA, Australia and New Zealand to participate in a 12-month study, designed to evaluate the efficacy of dimebon when added to ongoing AD treatment with donepezil (Pfizer Inc. and Medivation Inc., 2015). The results of this trial were unfortunately negative yet again, which proves detrimental for dimebon as an AD therapy, and further highlights the difficulties scientists face in finding potential treatments for diseases like AD. Conclusion Mitochondrial dysfunction is an early feature of AD pathology. Any damage to mitochondria by either Aβ or ROS can result in interrupting the usual mechanisms by which ROS are destroyed, therefore further increasing the number of ROS present in the organelle. It has been found that in post-mortem AD brains there is a deficit of COX, the terminal enzyme in the mitochondrial respiratory chain responsible for reducing oxygen radicals, supporting the theory that ROS are involved in the mitochondrial damage found in AD. Many antioxidants have been investigated as therapies for AD, and further studies have been carried out to find mitochondria specific antioxidants to enable a greater concentration of antioxidants to accumulate in the mitochondria, allowing a more specific method for combatting mitochondrial oxidative stress. It has been suggested that as early as 2025, prevention or effective treatment of AD may be realized (Cummings et al., 2016). Steps along this road include finding therapies that inhibit primary progenitors, reduce secondary symptoms, slow AD progression and ultimately repair damaged neurons (Feng and Wang, 2012). Further study of both generic and mitochondria specific antioxidants should be carried out to find more potential treatment strategies for Aβ induced neurotoxicity in AD and other neurodegenerative diseases. Acknowledgements Many thanks to Jane Armstrong, Mark Davies and Nicolas Haroune for helpful comments on earlier drafts of this work. Author biography Zoe L. Hawking recently graduated the University of Sunderland's BSc Biomedical Sciences degree in July 2016 with a first class honours. This review is largely unmodified from her level 5 biosciences literature review. Zoe has particular interests in both Alzheimer's disease and cancer and hopes to pursue a career in cancer biology. References Annamalai , B. , Won , J. S., Choi , S. et al. . ( 2015 ) Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation , Biochemical and Biophysical Research Communications , 29 ( 15 ), 132 – 141 . Google Scholar OpenURL Placeholder Text WorldCat Ankarcrona , M. , Mangialasche , F. and Winblad , B. ( 2010 ) Rethinking Alzheimer's disease therapy: are mitochondria the key . Journal of Alzheimer's Disease , 20 ( 2 ), 579 – 590 . Google Scholar OpenURL Placeholder Text WorldCat Arai , T. , MacKenzie , I. R., Hasegawa , M. et al. . ( 2009 ) Phosphorylated TDP-43 in Alzheimer's disease and dementia with lewy bodies , Acta Neuropathologica , 117 ( 2 ), 125 – 136 . Google Scholar Crossref Search ADS PubMed WorldCat Bachurin , S. O. , Bukatina , E., Lermontova , N. N. et al. . ( 2001 ) Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer , Annals of the New York Academy of Sciences , 939 , 425 – 435 . Google Scholar Crossref Search ADS PubMed WorldCat Biswas , J. , Goswami , P., Gupta , S. et al. . ( 2015 ) Streptozotocin induced neurotoxicity involves Alzheimer's related pathological markers: a study on N2A cells , Molecular Neurobiology . DOI:10.1007/s12035-015-9144-z. Google Scholar OpenURL Placeholder Text WorldCat Bonda , D. J. , Wang , X., Perry , G. et al. . ( 2010 ) Mitochondrial dynamics in Alzheimer's disease: opportunities for future treatment strategies , Drugs Aging , 27 ( 3 ), 181 – 192 . Google Scholar Crossref Search ADS PubMed WorldCat Brunstromm , H. R. and Englund , E. M. ( 2009 ) Cause of death in patients with dementia disorders , European Journal of Neurology , 16 ( 4 ), 488 – 492 . Google Scholar Crossref Search ADS PubMed WorldCat Cacabelos , R . ( 2007 ) Donepezil in Alzheimer's disease: from conventional trials to pharmacogenetics , Neuropsychiatric Disease Treatment , 3 ( 3 ), 303 – 333 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Caspersen , C. , Wang , N., Yao , J. et al. . ( 2005 ) Mitochondrial abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease , The Journal of the Federation of American Societies for Experimental Biology (FASEB) , 19 ( 14 ), 2040 – 2041 . Google Scholar OpenURL Placeholder Text WorldCat Centers for Disease Control and Prevention, National Center for Health Statistics . Available at: http://wonder.cdc.gov/ucd-icd10.html [Accessed: 24 February 2015]. Chan , D. C . ( 2006 ) Mitochondrial fusion and fission in mammals , Annual Review of Cell and Developmental Biology , 22 , 79 – 99 . Google Scholar Crossref Search ADS PubMed WorldCat Christiane , R. , Brayne , C. and Mayeux , R. ( 2011 ) Epidemiology of Alzheimer Disease , Nature Reviews Neurology , 7 ( 3 ), 137 – 152 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Crouch , P. J. , Blake , R., Duce , J. A. et al. . ( 2005 ) Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta 1-42 , Journal of Neuroscience , 25 ( 3 ), 672 – 679 . Google Scholar Crossref Search ADS PubMed WorldCat Cullen , B. , O'Neill , B., Evans , J. J. et al. . ( 2007 ) A review of screening tests for cognitive impairment , Journal of Neurology, Neurosurgery and Psychiatry , 78 ( 8 ), 790 – 799 . Google Scholar Crossref Search ADS WorldCat Cummings , J. , Aisen , P. S., DuBois , B. et al. . ( 2016 ) Drug development in Alzheimer's disease: the path to 2025 , Alzheimer's Research and Therapy , 8 ( 1 ), 39 . Google Scholar Crossref Search ADS PubMed WorldCat Das , P. , Murray , B. and Belfort , G. ( 2015 ) Alzheimer's protective A2T mutation changes the conformational landscape of the Aβ1-42 monomer differently than does the A2V mutation , Biophysical Journal , 108 ( 3 ), 738 – 747 . Google Scholar Crossref Search ADS PubMed WorldCat Department of Economic and Social Affairs . ( 2001 ) World Population Ageing: 1950–2050 , USA, United Nations , New York . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC Devi , L. , Prabhu , B. M., Galati , D. F. et al. . ( 2006 ) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction , Journal of Neuroscience , 26 ( 35 ), 9057 – 9068 . Google Scholar Crossref Search ADS PubMed WorldCat Diana , A. , Simic , G., Sinforiani , E. et al. . ( 2008 ) Mitochondria morphology and DNA content upon sublethal exposure to beta-amyloid (1-42) peptide , Collegium Antropologicum , 32 ( 1 ), 51 – 58 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Dias , V. , Junn , E., Mouradian , M. M. ( 2013 ) The role of oxidative stress in Parkinson's Disease , Journal of Parkinson's Disease , 3 ( 4 ), 461 – 491 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Doody , R. S. , Gavrilova , S. I., Sano , M. et al. . ( 2008 ) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , Lancet , 372 ( 9634 ), 207 – 215 . Google Scholar Crossref Search ADS PubMed WorldCat Dysken , M. W. , Sano , M., Asthana , S. et al. . ( 2014 ) Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial , The Journal of the American Medical Association , 311 ( 1 ), 33 – 44 . Google Scholar Crossref Search ADS PubMed WorldCat Fargo , K. N. , Aisen , P., Albert , M. et al. . ( 2014 ) 2014 report on the milestones for the US national plan to address Alzheimer's disease , The Journal of the Alzheimer's Association , 10 ( 5 ), 430 – 452 . Google Scholar Crossref Search ADS WorldCat Farlow , M. R. , Sadowsky , C. H., Velting , D. M. et al. . ( 2015 ) Evaluating response to high-dose 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease , CNS Neuroscience and Therapeutics , 21 ( 6 ), 513 – 519 . Google Scholar Crossref Search ADS PubMed WorldCat Farokhnia , M. , Sabet , M. S., Iranpour , N. et al. . ( 2014 ) Comparing the efficacy and safety of Crocus Sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial , Human Psychopharmacology: Clinical and Experimental , 29 , 351 – 359 . Google Scholar Crossref Search ADS WorldCat Feng , Y. and Wang , X. ( 2012 ) Antioxidant therapies for Alzheimer's disease , Oxidative Medicine and Cellular Longevity , 2012 , 1 – 17 . Google Scholar Crossref Search ADS WorldCat Gillardon , F. , Rist , W., Kussmaul , L. et al. . ( 2007 ) Proteomic and functional alterations in brain mitochondria from Tg2576 mice occur before amyloid plaque deposition , Proteomics , 7 ( 4 ), 605 – 616 . Google Scholar Crossref Search ADS PubMed WorldCat Gomes , M. J. , Martins , S. and Sarmento , B. ( 2015 ) siRNA as a tool to improve the treatment of brain diseases: mechanism, targets and delivery , Ageing Research Reviews , 21 , 43 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Grigorev , V. V. , Dranyi , O. A. and Bachurin , S. O. ( 2003 ) Comparative study of reaction mechanisms of dimebon and memantine on AMPA- and NDMA-subtypes glutamate receptors in rat cerebral neurons , Bulletin of Experimental Biology and Medicine , 136 ( 5 ), 474 – 477 . Google Scholar Crossref Search ADS PubMed WorldCat Guernsey , D. L. , Jiang , H., Campagna , D. R. et al. . ( 2009 ) Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia , Nature Genetics , 41 ( 6 ), 651 – 653 . Google Scholar Crossref Search ADS PubMed WorldCat Guzman-Martinez , L. , Farias , G. A. and Maccioni , R. B. ( 2013 ) Tau oligomers as potential targets for Alzheimer's disease and novel drugs , Frontiers in Neurology , 4 , 167 . Google Scholar Crossref Search ADS PubMed WorldCat Hager , K. , Marahrens , A., Kenklies , M. et al. . ( 2001 ) Alpha-lipoic acid as a new treatment option for Alzheimer type dementia , Archives of Gerontology and Geriatrics , 32 ( 3 ), 275 – 282 . Google Scholar Crossref Search ADS PubMed WorldCat Hansson-Peterson , C. A. , Alikhani , H., Behbahani , H. et al. . ( 2008 ) The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae , Proceedings of the National Academy of Sciences of the United States of America , 105 ( 35 ), 13145 – 13150 . Google Scholar Crossref Search ADS PubMed WorldCat Hayden , E. Y. and Teplow , D. B. ( 2013 ) Amyloid β-protein oligomers and Alzheimer's disease , Alzheimer's Research and Therapy , 5 ( 6 ), 60 . Google Scholar Crossref Search ADS PubMed WorldCat Herholz , K . ( 2008 ) Acetylcholinesterase activity in mild cognitive impairment and Alzheimer's disease , European Journal of Nuclear Medicine and Molecular Imaging , 35 ( 1 ), 25 – 29 . Google Scholar Crossref Search ADS WorldCat Hurd , M. D. , Martorell , P., Delavande , A. et al. . ( 2013 ) Monetary costs of dementia in the United States , The New England Journal of Medicine , 368 ( 14 ), 1326 – 1334 . Google Scholar Crossref Search ADS PubMed WorldCat Jain , V. , Langham , M. C. and Wehrli , F. W. ( 2010 ) MRI estimation of global brain oxygen consumption rate , Journal of Cerebral Blood Flow and Metabolism , 30 ( 9 ), 1598 – 1607 . Google Scholar Crossref Search ADS PubMed WorldCat Knott , A. B. and Bossy-Wetzel , E. ( 2008 ) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration , Annals of the New York Academy of Sciences , 1147 , 283 – 292 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , S. and Bandyopadhyay , U. ( 2005 ) Free heme toxicity and its detoxification systems in human , Toxicology Letters , 157 ( 3 ), 175 – 188 . Google Scholar Crossref Search ADS PubMed WorldCat Kumar , A. and Singh , A. ( 2015 ) A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions , Frontiers in Pharmacology , 6 , 206 . Google Scholar Crossref Search ADS PubMed WorldCat Lacker , L. L . ( 2013 ) Determining the shape and cellular distribution of mitochondria: the integration of multiple activities , Current Opinion in Cell Biology , 25 ( 4 ), 471 – 476 . Google Scholar Crossref Search ADS PubMed WorldCat Leifer , B. P . ( 2009 ) Alzheimer's disease: seeing the signs early , Journal of the American Academy of Nurse Practitioners , 21 ( 11 ), 588 – 595 . Google Scholar Crossref Search ADS PubMed WorldCat Lermontova , N. N. , Redkozubov , A. E., Shevstova , E. F. et al. . ( 2001 ) dimebon and tacrine inhibit neurotoxic action of beta-amyloid culture and block L-Type Ca2+ channels , Bulletin of Experimental Biology and Medicine , 132 ( 5 ), 1079 – 1083 . Google Scholar Crossref Search ADS PubMed WorldCat Lezi , E. and Swerdlow , R. H. ( 2012 ) Mitochondria in neurodegeneration , Advances in Experimental Medicine and Biology , 942 , 269 – 286 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lovell , M. A. , Xiong , S., Xie , C. et al. . ( 2004 ) Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3 , Journal of Alzheimer's Disease , 6 ( 6 ), 659 – 671 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lustbader , J. W. , Cirilli , M., Lin , C. et al. . ( 2004 ) ABAD directly links abeta to mitochondrial toxicity in Alzheimer's disease , Science , 304 ( 5669 ), 448 – 452 . Google Scholar Crossref Search ADS PubMed WorldCat Maczurek , A. , Hager , K., Kenklies , M. et al. . ( 2008 ) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease , Advanced Drug Delivery Reviews , 60 ( 13-14 ), 1463 – 1470 . Google Scholar Crossref Search ADS PubMed WorldCat Mandemakers , W. , Morais , V. A. and De Strooper , B. ( 2007 ) A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases , Journal of Cell Science , 120 ( 10 ), 1707 – 1716 . Google Scholar Crossref Search ADS PubMed WorldCat Mantoani , S. P. , Chierrito , T. P., Vilela , A. F. et al. . ( 2016 ) Novel triazole-quinoline derivatives as selective dual binding site acetylcholinesterase inhibitors , Molecules , 21 ( 2 ), 193 . Google Scholar Crossref Search ADS WorldCat McManus , M. J. , Murphy , M. P. and Franklin , J. L. ( 2011 ) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathy in a transgenic mouse model of Alzheimer's disease , Journal of Neuroscience , 31 ( 44 ), 15703 – 15715 . Google Scholar Crossref Search ADS PubMed WorldCat Menting , K. W. and Claassen , J. A. H. R. ( 2014 ) β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease , Frontiers in Ageing Neuroscience , 6 ( 165 ). 10.3389/fnagi.2014.00165. Google Scholar OpenURL Placeholder Text WorldCat Mitoq.com . MitoQ. [Image] [Online] Available at: http://commons.wikimedia.org/wiki/File%3AMitoq_Accumulation.jpg [Accessed: 7 April 2015]. Mohammadi-Khanaposhtani , M. , Saeedi , M., Zafarghandi , N. S. et al. . ( 2015 ) Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation and docking study of acridone linked to 1,2,3-triazole derivatives , European Journal of Medical Chemistry , 92 , 799 – 806 . Google Scholar Crossref Search ADS WorldCat Mushtag , G. , Greig , N. H., Khan , J. A. et al. . ( 2014 ) Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus , CNS & Neurological Disorders Drug Targets , 13 ( 8 ), 1432 – 1439 . Google Scholar Crossref Search ADS PubMed WorldCat Mutisya , E. M. , Bowling , A. C. and Beal , M. F. ( 1994 ) Cortical cytochrome oxidase activity is reduced in Alzheimer's disease , Journal of Neurochemistry , 63 ( 6 ), 2179 – 2184 . Google Scholar Crossref Search ADS PubMed WorldCat Ng , L. F. , Gruber , J., Cheah , I. K. et al. . ( 2014 ) The mitochondria targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease , Free Radical Biology and Medicine , 71 , 390 – 401 . Google Scholar Crossref Search ADS PubMed WorldCat NHS UK , 2015 . Tests for Diagnosing Dementia. [Online] Available at: http://www.nhs.uk/conditions/dementia-guide/pages/dementia-diagnosis-tests.aspx [Accessed: 1 December 2015]. Obashi , K. and Okabe , S. ( 2013 ) Regulation of mitochondrial dynamics and distribution by synapse position and neuronal activity in the axon , European Journal of Neuroscience , 38 ( 3 ), 2350 – 2363 . Google Scholar Crossref Search ADS PubMed WorldCat Obregon , D. , Hou , H., Deng , J. et al. . ( 2012 ) sAPP-α modulates β-secretase activity and amyloid-β generation , Nature Communications , 10 ( 3 ), 777 . Google Scholar Crossref Search ADS WorldCat O'Brien , R. J. and Wong , P. C. ( 2011 ) Amyloid precursor protein processing and Alzheimer's disease , Annual Review of Neuroscience , 34 , 185 – 204 . Google Scholar Crossref Search ADS PubMed WorldCat Obulesu , M. and Lakshmi , M. J. ( 2014 ) Apoptosis in Alzheimer's disease: an understanding of the physiology, pathology and therapeutic avenues , Neurochemical Research , 39 ( 12 ), 2301 – 2312 . Google Scholar Crossref Search ADS PubMed WorldCat Padurariu , M. , Ciobica , A., Lefter , R. et al. . ( 2013 ) The oxidative , Stress Hypothesis in Alzheimer's Disease , 25 ( 4 ), 401 – 409 . Google Scholar OpenURL Placeholder Text WorldCat Perez , S. E. , Nadeem , M., Sadleir , K. R. et al. . ( 2012 ) Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice , International Journal of Physiology, Pathophysiology and Pharmacology , 4 ( 3 ), 115 – 127 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Picone , P. , Nuzzo , D., Caruana , L. et al. . ( 2014 ) Mitochondrial dysfunction: different routes to Alzheimer's disease therapy , Oxidative Medicine and Cellular Longevity , 2014 , 1 – 11 . Google Scholar Crossref Search ADS WorldCat Pfizer Press Inc. and Medivation Inc . ( 2010 ). Pfizer and medivation announce results from two phase 3 studies in Dimebon (Latrepirdine*) Alzheimer's disease clinical development program. [Online] Available at: http://investors.medivation.com/releasedetail.cfm?releaseID=448818 [Accessed: 10 April 2015]. Pfizer Press Inc. and Medivation Inc . ( 2015 ). Pfizer and medivation initiate phase 3 trial of dimebon added to donepezil in patients with Alzheimer's disease. [Online] Available at: http://www.prnewswire.com/news-releases/pfizer-and-medivation-initiate-phase-3-trial-of-dimebon-added-to-donepezil-in-patients-with-alzheimers-disease-61820322.html [Accessed: 19 April 2015]. Qiu , C. , Kivipelto , M. and von Strauss , E. ( 2009 ) Epidemiology of Alzheimer's disease: occurrence, determinants and strategies toward intervention , Dialogues in Clinical Neuroscience , 11 ( 2 ), 111 – 128 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Revel , F. , Gilbert , T., Roche , S. et al. . ( 2015 ) Influence of oxidative stress on cognitive decline , Journal of Alzheimer's Disease , 45 ( 2 ), 553 – 560 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Rui , Y. , Tiwari , P., Xie , Z. et al. . ( 2006 ) Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons , Journal of Neuroscience , 26 ( 41 ), 10480 – 10487 . Google Scholar Crossref Search ADS PubMed WorldCat Sadowsky , C. H. , Micca , J. L., Grossberg , G. T. et al. . ( 2014 ) Rivastigmine from capsule to patch: therapeutci advances in the management of Alzheimer's disease and Parkinson's disease dementia , The Primary Care Companion for CNS Disorders , 16 ( 5 ), 1654 – 1662 . Google Scholar OpenURL Placeholder Text WorldCat Santos , R. X. , Correia , S. C., Wang , X. et al. . ( 2010 ) a synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease , Journal of Alzheimer's Disease: JAD , 20 ( 2 ), 401 – 412 . Google Scholar OpenURL Placeholder Text WorldCat Sasaki , S. and Horie , Y. ( 2014 ) The effects of an uninterrupted switch from donepezil to galantamine without dose titration on behavioral and psychological symptoms of dementia in Alzheimer's disease , Dementia and Geriatric Cognitive Disorders Extra , 4 ( 2 ), 131 – 139 . Google Scholar Crossref Search ADS PubMed WorldCat Schaffhauser , H. , Mathiasen , J. R., DiCamillo , A. et al. . ( 2009 ) Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities , Biochemical Pharmacology , 78 ( 8 ), 1035 – 1042 . Google Scholar Crossref Search ADS PubMed WorldCat Schwab , C. , Arai , T., Hasegawa , M. et al. . ( 2008 ) Colocalization of transactivation-responsive DNA binding protein 43 and huntingtin in inclusions of huntington disease , Journal of Neuropathology and Experimental Neurology , 67 ( 12 ), 1159 – 1165 . Google Scholar Crossref Search ADS PubMed WorldCat Shetty , R. A. , Ikonne , U. S., Forster , M. J. and Sumien , N. ( 2014 ) Coenzyme Q10 and α-tocopherol reversed age-associated functional impairments in mice , Experimental Gerontology , 2014 , 208 – 218 . Google Scholar Crossref Search ADS WorldCat Smith , R. A. , Hartley , R. C., Cocheme , H. M. et al. . ( 2012 ) Mitochondrial pharmacology , Trends in Pharmacological Sciences , 33 , 341 – 352 . Google Scholar Crossref Search ADS PubMed WorldCat Sperling , R. A. , Aisen , P. S., Beckett , L. A. et al. . ( 2011 ) Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , Alzheimer's & Dementia , 7 ( 3 ), 280 – 292 . Google Scholar Crossref Search ADS WorldCat Tamagno , E. , Parola , M., Bardini , P. et al. . ( 2005 ) β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress activated protein kinases pathways , Journal of Neurochemistry , 92 ( 3 ), 628 – 636 . Google Scholar Crossref Search ADS PubMed WorldCat Walsh , D. M. and Selkoe , D. J. ( 2007 ) Aβ oligomers: a decade of discovery , Journal of Neurochemistry , 101 ( 5 ), 1172 – 1184 . Google Scholar Crossref Search ADS PubMed WorldCat Wang , X. , Su , B., Zheng , L. et al. . ( 2009 ) The role of mitochondrial dynamics in the pathogenesis of Alzheimer's disease , Journal of Neurochemistry , 109 , 153 – 159 . Google Scholar Crossref Search ADS PubMed WorldCat Wenk , G. L. , Parsons , C. G. and Danysz , W. ( 2006 ) Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine , Behavioural Pharmacology , 17 , 411 – 424 . Google Scholar Crossref Search ADS PubMed WorldCat Yamashita , M. , Nonaka , T., Arai , T. et al. . ( 2009 ) Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models , FEBS Letters , 583 ( 14 ), 2419 – 2424 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , H. , Zhang. , Y., Chen , Y. et al. . ( 2012 ) Appoptosin is a novel proapoptotic protein and mediates cell death in neurodegeneration , The Journal of Neuroscience , 32 ( 44 ), 15565 – 15576 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang , Y. , Thompson , R., Zhang , H. et al. . ( 2011 ) APP processing in Alzheimer's disease , Molecular Brain, 4 (3) . DOI:10.1186/1756-6606-4-3. Google Scholar OpenURL Placeholder Text WorldCat Zhou , A. , Wu , H., Pan , J. et al. . ( 2015 ) Synthesis and evolution of paeonol derivatives as potential multifunctional agents for the treatments of Alzheimer's disease , Molecules , 20 ( 1 ), 1304 – 1318 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu , M. , Xiao , S., Li , G. et al. . ( 2013 ) Effectiveness and safety of generic memantine hydrochloride manufactured in china in the treatment of moderate to severe Alzheimer's disease: a multicenter, double-blind randomized controlled trial , Shanghai Archives of Psychiatry , 25 ( 4 ), 244 – 253 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Ziegler , D. , Reljanovic , M., Mehnert , H. et al. . ( 1999 ) Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials , Experimental and Clinical Endocrinology & Diabetes , 107 ( 7 ), 421 – 430 . Google Scholar Crossref Search ADS WorldCat Author notes † Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. Supervisor: Prof MS Davies, Faculty of Applied Sciences, University of Sunderland, Sunderland SR1 3 SD, UK. © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com © The Author 2016. Published by Oxford University Press.

Journal

BioScience HorizonsOxford University Press

Published: Jan 1, 2016

There are no references for this article.