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An effective treatment for Alzheimer's disease must consider both amyloid and tau

An effective treatment for Alzheimer's disease must consider both amyloid and tau BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu002 Review An effective treatment for Alzheimer’s disease must consider both amyloid and tau Claire J. Lansdall* School of Biomedical Science, University of Leeds, Leeds LS2 9JT, England *Corresponding author: Email: claire.lansdall@gmail.com Supervisor: Dr. Ian. C. Wood, School of Biomedical Science, University of Leeds, Leeds LS2 9JT, England. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting in cognitive impairment, loss of executive functions and progressive dementia. AD is the most common cause of dementia and incidence is increasing, probably due to a rapidly ageing population. Despite research efforts and a substantial unmet medical need, no effective cure has been identi - fied and treatment remains symptomatic. In this review, I assess the current status of AD research and examine future approaches for the development of a potential disease-modifying treatment. Research has focused primarily on amyloid pathology, after a correlation was discovered between mutations in several genes associated with amyloid processing and AD. The Amyloid Cascade Hypothesis suggests that increased amyloid beta (Aβ) aggregation is the major cause of AD, triggering the toxic events that lead to progressive neurodegeneration. However, no drug candidate targeting the cascade has yet pro- duced a successful treatment. It is now speculated that treatment requires early targeting of Aβ, when pathology remains reversible, and clinical trials are focusing on assessing Aβ compounds in pro-dromal AD. Lack of an effective A β-focused treat- ment has resulted in the consideration of hyperphosphorylated neurofibrillary tangles of tau (NFT), another major pathologi - cal hallmark of AD. Studies have repeatedly demonstrated a strong correlation between NFT build up and cognitive decline, and recent studies have identified a number of tau genetic markers associated with AD. Compounds preventing the hyper - phosphorylation of tau may therefore halt disease progression; however, the failure of previous tauopathy trials in progres- sive supranuclear palsy (PSP) has highlighted potential set-backs. The importance of tau as an independent cause of AD, and therefore a target for treatment, may be clarified by ongoing tau-focused clinical studies. Although A β and tau are both highly relevant, their relationship in causing AD remains unknown. Amyloid- and tau-targeting treatments may individually prove effective, however the convergent progression of A β and tau pathology suggests combination therapy may eventually be required, particularly in late stages of disease when both are abundant. While ongoing work focuses on single target thera- pies, a dual Aβ and tau targeting approach may be more likely to produce a breakthrough. Key words: Alzheimer’s disease (AD), amyloid beta (Aβ), tau, neurodegeneration, tauopathy, dementia Submitted on 20 November 2013; accepted on 12 May 2014 Introduction causing the brains of patients to weigh up to one-third less than that of an age-matched non-demented individual Alzheimer’s disease (AD) is an age-related, neurodegenerative (Laferla, Green and Oddo, 2007). AD is the most common disorder characterized by progressive neuronal loss in areas cause of dementia, accounting for approximately 60–80% of of the brain associated with cognitive learning and memory. all cases (AD Facts and Figures, 2010). It is estimated that AD occurs due to a combination of pathological changes in 35.6 million people worldwide suffer from dementia, with the brain which result in severe neuronal and synaptic loss, numbers expected to double every 20 years (Prince et al., © The Author 2014. 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/3.0/), 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  Review Bioscience Horizons • Volume 7 2014 2013; WHO, 2012). As well as the substantial personal cost, the hypothesis that the Amyloid Cascade is an insufficient tar - the total estimated worldwide financial burden of dementia get for the treatment of AD, and development of a potential was $604 billion in 2010 (Wimo et al., 2013). cure must consider both amyloid and tau pathology together. Extracellular amyloid beta (Aβ) aggregates, and intracel- lular hyperphosphorylated neurofibrillary tangles (NFT) of The Amyloid Cascade Hypothesis tau, constitute the two major pathological hallmarks of AD The Amyloid Cascade Hypothesis identifies A β aggregation (reviewed by Finder, 2010). These characteristic pathologies or decreased Aβ clearance as a trigger of the toxic events lead- have resulted in the proposal of two theories regarding the ing to substantial neurodegeneration (Hardy and Higgins, cause of AD. The Amyloid Cascade Hypothesis identifies 1992; Hardy and Selkoe, 2002). Aβ is generated through the increased Aβ aggregation or decreased Aβ clearance as the proteolytic processing of the type 1 integral membrane glyco- primary cause of disease, developing years prior to clinical protein, amyloid precursor protein (APP) (Finder, 2010). APP onset (Hardy and Higgins, 1992; Hardy and Selkoe, 2002). was identified in 1987 ( Kang et al., 1987) and duplication of Accumulation of pathogenic Aβ peptide species and insoluble the APP locus was subsequently reported to cause autosomal- plaque formation is believed to trigger a number of detrimen- dominant early-onset AD and cerebral amyloid angiopathy tal processes, including hyperphosphorylation of tau, which (CAA) (Rovelet-Lecrux et al., 2006). Processing of APP to Aβ lead to neuronal death (reviewed by Pimplikar, 2009). The occurs via one of the two major pathways, the amyloidogenic Tau Hypothesis is based on evidence that tau tangle pathology pathway and the non-amyloidogenic pathway, through cleav- occurs prior to Aβ plaque formation and more closely corre- age by a group of enzymes called alpha (α), beta (β) and lates with disease progression and severity than Aβ plaque gamma (γ) secretases. It is now widely accepted that Aβ occurs load (Braak and Braak, 1991). Although the mechanism by in two predominant forms, Aβ1-40 and Aβ1-42, sharing a which Aβ and tau interact remains uncertain (Ittner and Gotz, common N-terminus but differing in their carboxy-termini 2011), evidence has implicated both to be causative of AD. (Younkin, 1998; Jankowsky et al., 2004). AD results in a spectrum of symptoms including mild cogni- Under normal, non-pathological circumstances, the non- tive impairment, deficits in short-term and spatial memory, amyloidogenic pathway predominates, resulting in the cleav- emotional imbalances, loss of executive functions and progres- age of APP by α-γ-secretases. This pathway precludes sive dementia (reviewed by Pimplikar, 2009; Singh et al., deposition of intact Aβ peptide by producing a smaller, less 2012). The disease can be divided into two main categories, amyloidogenic form of Aβ only 40 residues in length (Aβ1- sporadic late-onset AD (LOAD) and early-onset familial AD 40), which is less likely to aggregate and cause toxicity (Jarrett, (FAD) (Finder, 2010). FAD accounts for less than 1% of all Berger and Lansbury, 1993). Under pathogenic circumstances, cases (AD Facts and Figures, 2010), with onset occurring APP is cleaved by β-γ-secretases to produce the more amy- between the ages of 55 and 65 due to genetic predisposition loidogenic Aβ1-42, the major species detected in the brains of (Bird, 1999). Although uncommon, mutations identified to AD patients (Iwatsubo, 1998; Finder and Glockshuber, 2007). cause FAD have provided important insights into the potential Overproduction of Aβ1-42 has been reported to cause FAD causes of sporadic AD, for which the greatest risk factor is age- and is speculated to be a cause of sporadic AD (Younkin, ing (Finder, 2010). FAD mutations implicated Aβ as a primary 1998). Aβ1-42 is considered pathogenic due to its greater cause of disease, resulting in the Amyloid Cascade Hypothesis hydrophobicity and longer length of 42 residues (Jarrett, becoming the dominant focus of research. However, failure to Berger and Lansbury, 1993). develop an Aβ targeting compound into a successful treatment for AD has cast doubt upon its relevance, resulting in the Tau Processing of APP by γ-secretase activity constitutes the Hypothesis re-surfacing. There are currently a number of final step in the release of both A β1-40 and Aβ1-42 (Herreman ongoing clinical trials assessing the ability of tau inhibitors to et al., 2000). Two genes, Presenilin 1 (PSEN1) and Presenilin reduce AD progression (ClinicalTrials.gov Identifiers: 2 (PSEN2), encode for the proteins presenilin 1 (PS1) and NCT01689233 and NCT01689246). Definitive conclusions presenilin 2 (PS2), respectively, both of which contribute to regarding the relevance of these tau-based drug candidates lie the secretase complex. Mutations in these genes have been with the completion and publication of clinical trial results. identified as being correlative of AD ( Younkin, 1998). Despite substantial efforts in drug development and an increased understanding of the underlying pathology of AD, The Tau Hypothesis no effective treatment has yet been identified. All currently The Tau Hypothesis identifies tau hyperphosphorylation as an approved drugs target symptoms and improve quality of life independent and primary cause of AD, due to observations that rather than modify disease progression. These treatments have tau tangle pathology occurs prior to Aβ plaque formation and relatively short-term, limited benefits ( Takeda et al., 2006; that NFT load more closely correlates with disease progression Raina et al., 2008) and emphasize the urgent need to continue and severity than plaque load (Braak and Braak, 1991). Alois the research efforts. Repeated failures to develop an effective, Alzheimer first reported his findings of NFT in 1907 ( Alzheimer, disease-modifying therapeutic, suggests the need to re-think 1907), and a correlation between tangle formation and the current approach to AD treatment. This review considers 2 Bioscience Horizons • Volume 7 2014 Review Alzheimer’s dementia was identified in 1968 ( Blessed, Tomlinson Genetics and Roth, 1968). The structure and composition of these char- Supporting evidence for the Amyloid Cascade Hypothesis acteristic tangles were not established until 1988 (Goedert et al., was provided by the mapping of several Aβ-increasing FAD 1988). In AD brains, hyperphosphorylated tau is the major mutations to the APP gene (Owen et al., 1990) and the pre- component of both NFTs in pyramidal neurons, and neuropil disposition of Down’s syndrome patients to AD due to ele- threads in distal dendrites (Finder, 2010). NFTs are filamentous vated lifetime APP production (Glenner and Wong, 1984; inclusions of tau which occur both in AD and in other tauopa- Rovelet-Lecrux et al., 2006). thies (Lee, Goedert and Trojanowski, 2001; Querfurth and LaFerla, 2010). Under normal conditions, tau is a soluble, abun- Studies have identified over-expression of APP, and subse - dant protein found in axons, which maintains assembly and quent generation of the Aβ1-42 peptide, to be central to neu- stability of microtubules and vesicular transport (Finder, 2010; ronal degeneration observed in AD (Skaper, 2012). Down’s Querfurth and LaFerla, 2010). Microtubule-associated tau pro- syndrome patients present with elevated APP, due to triplica- tein has been reported to be critical for normal neuronal activity tion of chromosome 21 (the location of the APP gene), and in the mammalian brain (Iqbal et al., 2005). develop increased Aβ accumulation in early life (Singh et al., 2012). Such patients often develop AD in their 30s, suggest- Phosphorylation and dephosphorylation of tau is regu- ing that increasing Aβ production predisposes individuals to lated by various kinases and phosphatases that add or remove AD (Singh et al., 2012). phosphate residues, respectively (Iqbal et al., 2005; Querfurth and LaFerla, 2010). Under pathological conditions, such as FAD, which typically manifests with an early-onset patho- AD and other tauopathies (Lee, Goedert and Trojanowski, genesis (Laferla, Green and Oddo, 2007), is characterized by 2001), hyperphosphorylation of tau results from both an similar Aβ pathology to sporadic AD, providing insights into imbalance in tau kinase and phosphatase activity and changes the possible causes of disease. A number of mutations, includ- in tau’s conformation (Iqbal et al., 2005). These changes ren- ing 32 APP missense mutations, over 150 PS1 mutations and der tau protein insoluble and reduce its affinity for microtu - 20 PS2 mutations, have been identified as correlative of AD bules, causing it to detach and spontaneously self-associate (Pimplikar, 2009; Finder, 2010). These mutations result in into paired helical filament structures ( Querfurth and either elevated production of total Aβ or a specific increase in LaFerla, 2010). These filaments then aggregate into NFTs, the levels of Aβ1-42, (Citron et al., 1992; Cai, Golde and disturbing and impairing axonal transport (Finder, 2010). Younkin, 1993; Bekris et al., 2010). Interestingly, protective Toxic forms of tau protein eventually ‘choke’ the neurone by mutations such as the A673T variant of APP, result in a 20% preventing the possibility of normal neuronal metabolism reduction in lifelong production of Aβ and prevent individu- and causing progressive neurodegeneration (Iqbal et al., als from developing cognitive impairments and AD (Jonsson 2005; Wischik et al., 2010). The resulting toxicity eventually et al., 2012). Therefore, mutations that increase Aβ produc- leaves behind only a marker of a previously existing neurone, tion predispose individuals to AD, whereas those that referred to as a ‘ghost’ tangle (Wischik et al., 2010). decrease Aβ appear protective. However, some PS1 muta- tions promote neurodegeneration and frontotemporal The amyloid hypothesis fails to dementia (FTD) without causing an increase in Aβ plaque explain all aspects of AD; evidence pathology or altering the Aβ40 to 42 ratio (Shioi et al., suggests tau may fill the gaps 2007), suggesting that their ability to cause neuronal toxicity in AD may be distinct from their effects on Aβ production. Studies have provided a wealth of supporting evidence for the Furthermore, no correlation between increased Aβ42, induced Amyloid Cascade Hypothesis, emphasizing Aβ to be a pri- by FAD mutants and age of disease onset was reported mary cause of AD. However, the pathogenic nature of Aβ has (Scheuner et al., 1996). Therefore, although some studies become increasingly questioned due to evidence reporting the provide strong evidence for the involvement of APP, PS1 and presence of Aβ plaques in healthy individuals, the lack of a PS2 in AD, they do not identify Aβ is the single primary cause defined pathogenic A β species and the repeated clinical fail- of disease. Indeed, reports of neuronal dysfunction via path- ures of Aβ targeting drug candidates (reviewed by Pimplikar, ways independent of APP and Aβ (Shioi et al. 2007; Baki 2009). Recent research suggests that NFT formation occurs et al., 2008) have reduced the focus on Aβ as the causative early and is a primary cause of toxicity (Wischik et al., 2010), agent of AD (Caughey and Lansbury, 2003, reviewed by whilst Aβ plaque formation may be a late-stage, neuroprotec- Pimplikar, 2009). tive event (reviewed by Maccioni et al., 2010). The theory that tau is an independent cause of AD is strengthened by Understanding the genetic basis of tau pathology in AD is observations that tau oligomers are directly toxic to neurons advancing rapidly. Initial evidence linking tau tangle forma- and tau pathology correlates with clinical cognitive decline in tion to neurodegeneration was provided by other tauopa- AD (Wischik et al., 2010). Tau hyperphosphorylation may be thies, displaying characteristics similar to AD. Tauopathies a convergent point of toxicity in the AD brain (Maccioni encompass a number of disorders, all of which result from et al., 2010), highlighting the potential for tau-targeting ther- the accumulation of abnormally hyperphosphorylated tau apeutics in clinical AD. and are associated with NFT formation and dementia (Iqbal 3 Review Bioscience Horizons • Volume 7 2014 et al., 2005). Over 30 mutations found on chromosome 17 the ERC, demonstrated a subsequent spreading of pathology (the location of the gene which encodes for tau, MAPT) are with ageing to regions of the brain innervated by ERC neu- associated with FTD and parkinsonism, supporting dysfunc- rons, particularly the hippocampus which is greatly affected tional tau protein as a primary cause of neurodegenerative in the later stages of AD (Liu et al., 2012). The spreading of disease (Goedert and Jakes, 2005). Identified mutations in tau pathology was found to be consistent with that seen upon MAPT reduce the ability of tau protein to interact with post-mortem examination of human AD brains (Liu et al., microtubules and increase its tendency to assemble into 2012). These findings suggest that tau-targeting treatments abnormal filaments ( Goedert and Jakes, 2005), consistent designed to inhibit the spreading of pathology in the early with tau pathology in sporadic AD. A recent genome-wide stages may have the potential to halt disease progression. association study found genetic markers associated with ele- vated levels of tau and phosphorylated tau in the cerebrospi- Animal models and clinical trials nal fluid of AD patients ( Cruchaga et al., 2013). Research led Identifying FAD mutations allowed AD to be modelled in by Dr. Alison Goate yielded particular genetic signals linked animals, although their usefulness remains controversial due to enhanced tau pathology in the brain and a faster rate of to the repeated failure of drugs effective in animal models to cognitive decline (Cruchaga et al., 2013). Although addi- treat AD in humans. Currently used animal models have been tional research is required to identify where these candidate developed using mutated APP, PS1 and MAPT genes, com- genes are expressed and whether more may be associated monly APP , PS1 and MAPT (Oddo et al., 2003). with tau-related pathology, the results highlight the possibil- Swe M146V P301L These models develop plaques and tangles in an age- ity of novel therapeutic targets or alternative models of AD. dependent manner and closely represent human AD (Oddo In addition, the findings demonstrate the ability of tau et al., 2003; 2006; Filali et al., 2012). Importantly, mice pathology to cause AD independently of Aβ pathology. expressing a combination of mutant APP, PS1 and MAPT Pathophysiology genes display plaques and tangles, and a reduction of both Aβ and tau is required to ameliorate cognitive decline (Oddo The Amyloid Cascade Hypothesis fails to explain the poor et al., 2006). Aβ reduction alone failed to demonstrate correlation between plaque load and the degree of dementia improvement in the cognitive phenotype in both spatial and in humans (Terry et al., 1991). Although one study identified contextual learning and memory paradigms, highlighting the a correlation between cognitive dysfunction and Aβ plaque potential role of tau in cognitive decline in the presence of formation in the entorhinal cortex (ERC) (Cummings et al., concomitant Aβ pathology (Oddo et al., 2006). 1996), many have reported a weak and inconsistent, if any, relationship between Aβ pathology and cognitive decline As of May 2014, all Aβ-targeting treatments have failed to (Crystal et al., 1988; Arriagada et al., 1992). It was reported generate significant improvements when trialled in the clinic, by Crystal et al. (1988) that cortical senile plaque count did according to the ClinicalTrials.gov database (Table 1). Anti- not distinguish between demented and non-demented indi- amyloid immunotherapy became the focus of Aβ-targeting viduals. This was supported by reports of non-demented indi- research, following the finding that anti-amyloid monoclonal viduals presenting with significant plaque load upon autopsy antibodies dissolved Aβ aggregates and prevented their for- (Wischik et al., 2010). Live molecular imaging techniques mation in vitro (Solomon et al., 1996). However, Aβ immu- have since confirmed the presence of plaques in the brains’ of notherapy has been faced with a number of safety and efficacy cognitively normal individuals in vivo (Nordberg, 2008; drawbacks, including encephalitis, a lack of clinical improve- Villemagne et al., 2008). These findings suggest that plaques ment and an absence of effect on NFTs (Rosenmann, 2013). are not necessarily causative of memory deficits, indicating As a central role of NFTs in dementia is becoming more flaws in the Amyloid Cascade Hypothesis. Importantly, the apparent, it is likely that clearance of amyloid pathology is lack of correlation between plaque load and cognition has insufficient to improve dementia symptoms in AD patients. likely influenced the clinical failure of many A β-targeting ther- Indeed, although amyloid pathology has often been found to apeutics. However, recent data have suggested that the species be upstream of tau pathology, amyloid-toxicity has been of Aβ is important for toxicity, and that Aβ plaques may con- reported to be tau-dependent, highlighting the potential for stitute a less toxic aggregate (reviewed by Pimplikar, 2009). tau-targeting therapies to prevent both pathologies The exact role of Aβ in AD therefore remains unknown. (Rosenmann, 2013). Conversely, tau aggregation and the resultant brain lesions The failure of anti-amyloid trials has triggered discussions observed in AD have been repeatedly reported to correlate assessing the cause of drug candidate failure. Importantly, with clinical dementia and cell death (Iqbal et al., 2005; recent Phase III trials of bapineuzumab and solanezumab Wischik et al., 2010). Hyperphosphorylated tau is reported reported that approximately 25% of study patients diagnosed to spread in a clearly defined sequence, mapping clinically to with mild AD had negative positron emission tomography measurable stages of cognitive decline and physically to (PET) Aβ imaging (Karran & Hardy, 2014). As these patients stages of loss of brain function seen in AD patients (Braak lack Aβ pathology, they are unlikely to benefit from anti- and Braak, 1991; Braak et al., 2011). Transgenic mice amyloid treatments, therefore impacting the overall efficacy expressing human mutant MAPT predominantly in layer 2 of outcome of the study. In addition, many argue that the 4 Bioscience Horizons • Volume 7 2014 Review targeted patient population often presented with abundant treatment. Importantly, previous anti-amyloid trials (Table 1) and irreversible Aβ pathology at the time of the trials (Karran, have tested several compounds, each with distinct mechanisms Mercken and De Strooper, 2011). Karran, Mercken and De of action. It is therefore probable that different stages of the Strooper (2011) proposed an Aβ trigger scenario explaining disease process and various forms of Aβ have already been AD progression. They suggested that during disease progres- targeted, further emphasizing the failure of this approach. sion an Aβ deposition threshold is eventually reached, whereby Targeting Aβ alone at clinically relevant stages of AD, when there is sufficient ‘aggregate stress’ to initiate or accelerate Aβ and tau pathology are abundant, has so far appeared insuf- tau pathology, which then becomes self-sustaining and ficient to successfully treat the disease, probably due to its Aβ-independent. At this point, therapeutic intervention cannot highly complex, multi-factorial pathology. Ongoing be effective. Interest in this theory has initiated clinical trials preventative anti-amyloid investigations, including the testing individuals with early signs of dementia, termed pro- Dominantly Inherited Alzheimer’s Network (DIAN), dromal AD, who are considered at risk of developing AD Alzheimer’s Prevention Initiative (API) and Anti-Amyloid (Karran, Mercken and De Strooper, 2011). These trials present treatment in Asymptomatic Alzheimer’s Disease (A4) trials a huge clinical challenge, particularly regarding the selection (Carrillo et al., 2013), will provide further insights into early of the clinical trial population and ethical considerations. AD development and progression, and may answer the long- F. Hoffmann-La Roche Ltd. is currently assessing a monoclo- standing questions regarding the Amyloid Hypothesis. nal antibody that recognizes Aβ, gantenerumab, in patients within the prodromal phase (Ostrowitzki et al., 2012). The Tau-based drug discovery is advancing rapidly, although mechanism by which anti-amyloid antibodies remove Aβ from limited focus on tau in previous years has hindered the pro- the brain is speculated to be via effector cell-mediated phago- gression of such therapeutics to Phase III trials. A number of cytosis or direct dissolution of amyloid (Weiner and Frenkel, inhibitors of tau aggregation have already been identified, 2006). Gantenerumab is reported to cause Fc receptor/ with three distinct mechanisms of action (reviewed by microglia-mediated phagocytosis of amyloid, followed by Brunden, Trojanowski and Lee, 2009). Tau-based research lysosomal degradation (Bohrmann et al., 2012). If unsuccess- has focused primarily on compounds that either inhibit the ful in Phase III, this trial will suggest past failures are not due kinases responsible for phosphorylation of tau or inhibit to administration of Aβ-therapeutics too late in disease pro- the aggregation of tau. Compounds preventing the disasso- gression, confirming flaws in the A β-focused approach to AD ciation of tau from microtubules have also been investigated, Table 1. Progress of late-phase clinical trials targeting the Amyloid Cascade Hypothesis Drug type Drug name Phase Reason for failure Aβ aggregation Alzhemed™ Results obtained could not support a claim for clinical efficacy (ClinicalTrials.gov Identifier: III inhibitor (Tramiprosate) NCT00088673) Evaluated in two Phase III trials, the Interrupting Alzheimer’s dementia by evaluating treatment of amyloid pathology (IDENTITY ) trial and the IDENTITY-2 trial (ClinicalTrials.gov γ-Secretase identifier: NCT00594568 and NTC00762411). Patients receiving Semagacestat displayed an Semagacestat III Inhibitor increased deterioration in cognition and activities of daily living compared to placebo- treated controls. Semagacestat was also found to be associated with an increased risk of skin cancer compared to placebo (Karran, Mercken and De Strooper, 2011) γ-Secretase Flurizan™ No statistically significant effect in co-primary outcome measures of cognition and activities III modulators (tarenflurbil) of daily living was observed (ClinicalTrials.gov Identifier: NCT00105547) Safety findings were reported, including the development of aseptic meningoencephalitis Aβ active AN1792 III and leukoencephalopathy in 6% of vaccinated patients (ClinicalTrials.gov Identifier: immunotherapy NCT00021723) No significant efficacy found. Furthermore, vasogenic oedema was reported during the study, Aβ passive Bapineuzumab III particularly in ApoE4 carriers. Due to these safety findings, the highest dose was discontinued immunotherapy (ClinicalTrials.gov Identifier: NCT00575055 and NCT00574132; Salloway et al., 2014) Failed to reach its cognitive or functional endpoints in either of two double-blind, placebo- controlled trials in patients with mild to moderate Alzheimer’s disease EXPEDITION and Solanezumab III EXPEDITION-2 (ClinicalTrials.gov Identifier: NCT00905372 and NCT00904683, Siemers et al., 2010), despite acute and sub-chronic treatment attenuating or reversing memory deficits in transgenic mice (Imbimbo et al., 2012) Gantenerumab II/III Ongoing (Clinical Trials.gov identified NCT01224106, NCT02051608 and NCT01760005) Numerous failures and discontinuations have highlighted possible inconsistencies in the Amyloid Hypothesis. (Information from ClinicalTrials. gov, Alzforum.org, Rosenmann, 2013). 5 Review Bioscience Horizons • Volume 7 2014 although to a lesser extent (reviewed by Boutajangout by accumulating evidence from anti-tau immunotherapy, et al., 2011; Zhang et al., 2012). Glycogen synthase kinase demonstrated to effectively reduce tau-pathology and 3β (GSK3β), cyclin dependant kinase 5 (CdK5) and improve the symptoms of dementia in animal models, includ- microtubule-affinity-regulating kinase (MARK) have been ing motor function and cognitive decline (reviewed by reported to collectively represent the three major tau kinases Rosenmann, 2013). As tau-based drug development is some responsible for phosphorylation of tau (reviewed by 20 years behind Aβ, the advancement of current pre-clinical Geschwind, 2003; Chung, 2009). Substantial pre-clinical tau-targeting compounds to the clinic is highly anticipated work has demonstrated that GSK3 and CdK5 inhibitors can and may prove extremely informative. prevent tau hyperphosphorylation (reviewed by Bhat et al., 2008; Boutajangout, Sigurdsson and Krishnamurthy, 2011). Tau and amyloid interact to cause Tau-based immunotherapy has also emerged as a potential disease approach for reducing both Aβ and tau pathology and has been explored in animal studies (reviewed by Rosenmann, The relationship between Aβ and tau in AD pathogenesis 2013). Some of the most advanced tau-based therapeutics remains controversial. Although drug development has often being evaluated in the clinic are the tau aggregation inhibi- focused on targeting Aβ and tau pathology in isolation, both tors. Rember recently became the first tau-aggregation may require targeting for effective disease-modifying treat- inhibitor to be clinically investigated by TauRx , a company ment. Continued research into their interplay will provide dedicated to tau-based therapeutics (taurx.com). TauRx alternative methods for intervention. Current evidence from reported success in completed Phase II trials assessing in vitro and in vivo models suggests three possible mecha- Rember (ClinicalTrials.gov Identifier: NCT00515333) and nisms by which they interact (Fig. 1). subsequently initiated two ongoing Phase III trials assessing the second-generation drug LMTX™ (ClinicalTrials.gov Aβ is causative of some tau pathology Identifier: NCT01689233 and NCT01689246). However, lack of published data regarding the completed Phase II tri- Several studies have provided evidence that tau tangles can be als, along with the current absence of any additional conclu- induced by Aβ. Ferrari et al. (2003) reported that exposure to sive Phase III trials, highlights the need to be cautious when Aβ was sufficient to induce tau filament formation in a human considering the potential of tau-based therapeutics. tissue culture system, in the absence of mutations in tau Furthermore, the Allon small peptide davunetide, developed (Ferrari et al., 2003). Furthermore, mice with mutations in the to target tau pathology, failed to meet its primary and sec- genes encoding APP and tau displayed a sevenfold increase in ondary endpoints when evaluated in a Phase II/III study in NFTs, compared with mice with mutations only in the tau PSP (ClinicalTrials.gov Identifier: NCT01110720). Similarly, gene (Lewis et al., 2001). In the same study, Aβ plaque forma- tideglusib, a GSK-3 inhibitor developed by Noscira, failed to tion was unaffected by the presence of tau lesions (Lewis meet its co-primary endpoints in two separate Phase II stud- et al., 2001). Similarly, intracranial injection of Aβ42 fibrils ies in PSP and AD (del Ser et al., 2013; Tolosa et al., into mutant tau transgenic mice caused a fivefold increase in 2014; ClinicalTrials.gov Identifier: NCT01049399 and NCT01350362). However, tideglusib was reported to reduce global brain atrophy compared with placebo in the PSP study, with the largest effect seen in the parietal and occipital lobes, indicating a possible neuroprotective effect (Höglinger et al., 2014). Importantly, these brain areas are only minimally impacted in PSP, providing an explanation for the lack of clinical outcome in this population (Höglinger et al., 2014). The pilot study of tideglusib in AD reported trends towards cognitive improvement, although these failed to reach sta- tistical significance due to the small sample size ( del Ser et al., 2013). As tideglusib has been reported to target the frontal lobe and hippocampus, the potential of GSK-3 inhibitors in AD should be further explored (Höglinger et al., 2014). Tau-based therapeutics may still represent the first major breakthrough in disease-modifying treatment for AD; how- ever, such claims have yet to be supported by successful Phase Figure 1. Progression of AD pathology. Flow chart to depict the toxic III trials. Unlike Aβ-targeting therapeutics, targeting tau pathways reported to lead to development of AD. Whether Aβ is pathology may hold the potential to delay cognitive decline causative of tau pathology or vice versa is currently unknown. It at later stages in disease progression, when Aβ and tau appears likely that both eventually promote a pathway of neuronal pathology are present. This has been particularly supported degeneration, leading to progressive dementia and death. 6 Bioscience Horizons • Volume 7 2014 Review NFT pathology as early as 18 days post injection (Gotz et al., the significance of this claim (reviewed by Pimplikar, 2009). It 2001). This increase in AD-like tau pathology suggests that is now accepted that Aβ oligomers may be a more toxic form Aβ may be toxic via acceleration of tau hyperphosphoryla- of protein aggregation, with plaques being less relevant to dis- tion, supporting the theory that compounds targeting Aβ may ease progression, although research aimed at reducing Aβ be sufficient to treat AD by preventing tau pathology. plaques is still ongoing (ClinicalTrials.gov). However, at later stages in disease progression, when hyper- Aβ and Tau demonstrate synergistic effects phosphorylated tau is self-sustaining, Aβ-targeting therapeu- tics have proven ineffective. Importantly, tau aggregates can It has been suggested that tau and Aβ interact by targeting form in the absence of Aβ pathology, for example in FTD, different components of the same system to amplify each where mutations in tau-encoded MAPT genes result in the other’s toxic effects downstream (reviewed by Ittner and hyperphosphorylation of tau (Ballatore, Lee and Trojanowski, Gotz, 2011). An example of such synergistic effects is the 2007). However, it is possible that while mutant tau may cir- implication of both Aβ and tau in the impairment of cumvent the need for Aβ-induction of hyperphosphorylation, mitochondrial proteins related to complexes I and IV of wild-type tau may still require Aβ to trigger tangle formation. the oxidative phosphorylation system, in mice expressing It may also be argued that although diseases such as FTD pro- APP PS2 MAPT which display both Aβ and tau Swe N141I P301L vide important insights into tau-based pathology in AD, they pathology (Rhein et al., 2009). It was found that deregula- remain distinct from AD in their symptomatology and pathol- tion of complex I was tau-dependent, whereas deregulation ogy. Regardless, the observation that tau pathology can occur of complex IV was Aβ dependent, both at the protein and in the absence of prior Aβ pathology has enhanced research activity levels (Rhein et al., 2009). Therefore, by acting on into tau toxicity in isolation, building supportive evidence for the same system, tau and Aβ may enhance the downstream the theory that tau develops early and acts as a primary and toxic events related to AD. Although the mechanism of Aβ independent cause of AD. and tau interplay remains largely unknown, this provides evi- dence for a molecular link between the proteins and AD Tau is required for neurodegeneration pathology. It appears almost certain that they interact to and Aβ pathology either cause or enhance the progression of AD. Therefore, although no proof of concept is currently available, a com- With many Phase II and III clinical trials targeting Aβ failing bined therapy targeting both pathologies may eventually con- to produce a marketed treatment for AD (ClinicalTrials.gov), stitute the most effective approach to treatment. the view that tau is a secondary effect of Aβ pathology is becoming less favourable. Rapoport et al. (2002) reported that tau-depleted neurons showed no signs of degeneration in Conclusion the presence of Aβ, providing direct evidence to support an essential role for tau in the Aβ-mediated toxicity and neuro- As proof of a single dominant underlying cause of AD degeneration seen in AD (Rapoport et al., 2002). Furthermore, remains inconclusive, it is logical to accept that both tau and Ittner et al. (2010) reported that tau reduction blocked Aβ Aβ pathologies are highly influential. Considering this state - and excitotoxin-induced neuronal dysfunction. Although tau ment, a disease-modifying therapeutic must target both is predominantly found in axons, it is thought to have an pathological hallmarks. A range of drug candidates targeting important dendritic role that confers Aβ toxicity at the post Aβ alone have now been assessed, all of which have reported synapse through targeting of the Src Kinase FYN, a substrate limited success in clinical trials. Of these, immunotherapy of which is the NMDA receptor (Lee et al., 1998). Tau there- appears to most effectively target Aβ deposits in the brain, fore may be involved in the early-phases of AD, in contrast to despite failing to reduce cognitive decline. Supporters of the the widely accepted theory that tau is secondary to Aβ toxic- Amyloid Cascade Hypothesis have therefore emphasized the ity. Transgenic mice expressing truncated tau (tTau) or defi - potential of immunotherapy to treat early AD, before Aβ −/− cient in tau (Tau ) showed disruptions in postsynaptic pathology becomes irreversible (Karran, Mercken and De targeting to FYN, arresting Aβ-mediated excitotoxicity by Strooper, 2011). Indeed, observations of Aβ pathology in reducing interactions of NMDA receptors with postsynaptic years prior to clinical onset of dementia warrant continued density protein 95 (PSD95) (Ittner et al., 2010). Excitotoxicity clinical trials assessing Aβ-targeting therapeutics in prodro- is increasingly accepted as the mechanism by which Aβ exerts mal AD. Such ongoing trials will provide a definitive answer toxicity and, by blocking this mechanism using mice deficient regarding the relevance of treatment approaches targeting in tau or expressing truncated tau, memory deficits were pre - the Amyloid Hypothesis. Previous research has implicated vented and survival was improved (Ittner et al., 2010). Aβ as one of the major contributing factors rather than the Tau-initiated Aβ toxicity is further supported by the observa- sole cause of disease. Substantial research now implicates tion that NFT formation predates plaque formation (Braak hyperphosphorylated tau an independent cause of AD, et al., 1996), suggesting tau pathology may be present prior to and tau inhibitors are currently being investigated in clini- Aβ pathology. However, more recent research has suggested cal trials (ClinicalTrials.gov Identifier: NCT01689233 and that only certain forms of Aβ are inducers of tau pathology NCT01689246). Due to the current lack of published data and that Aβ plaques are a late-stage Aβ species, diminishing regarding these drug candidates, it remains premature to 7 Review Bioscience Horizons • Volume 7 2014 phosphatidylinositol 3-kinase neuroprotective signaling, The suggest that tau-based treatments will provide a cure for AD. Journal of Neuroscience, 28, 483–90. The outcome of the ongoing Phase III trials investigating tau inhibitors, along with continued research into tau genetic Ballatore, C., Lee, V. M. and Trojanowski, J. Q. 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Although bral grey matter of elderly subjects, The British Journal of Psychiatry, amyloid- and tau-targeting therapeutics may still indepen- 114, 797–811. dently prove successful, the highly complex nature of AD pathology suggests that effective intervention will not con- Bohrmann, B., Baumann, K., Benz, J. et al. (2012) Gantenerumab: a novel sist of a ‘one-drug wonder’, and a combined therapy will human anti-Aβ antibody demonstrates sustained cerebral almost certainly constitute the final step in the development amyloid-β binding and elicits cell-mediated removal of human amy- of a cure. loid, Journal of Alzheimer’s Disease, 28 (1), 49–69. Boutajangout, A., Sigurdsson, E. M. and Krishnamurthy, P. K. (2011) Tau Author biography as a therapeutic target for Alzheimer’s disease, Current Alzheimer Research, 8 (6), 666–77. Claire Lansdall received a First Class BSc Medical Sciences Honours Degree at the University of Leeds, England in 2013. Braak, H. and Braak, E. 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An effective treatment for Alzheimer's disease must consider both amyloid and tau

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu002 Review An effective treatment for Alzheimer’s disease must consider both amyloid and tau Claire J. Lansdall* School of Biomedical Science, University of Leeds, Leeds LS2 9JT, England *Corresponding author: Email: claire.lansdall@gmail.com Supervisor: Dr. Ian. C. Wood, School of Biomedical Science, University of Leeds, Leeds LS2 9JT, England. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder resulting in cognitive impairment, loss of executive functions and progressive dementia. AD is the most common cause of dementia and incidence is increasing, probably due to a rapidly ageing population. Despite research efforts and a substantial unmet medical need, no effective cure has been identi - fied and treatment remains symptomatic. In this review, I assess the current status of AD research and examine future approaches for the development of a potential disease-modifying treatment. Research has focused primarily on amyloid pathology, after a correlation was discovered between mutations in several genes associated with amyloid processing and AD. The Amyloid Cascade Hypothesis suggests that increased amyloid beta (Aβ) aggregation is the major cause of AD, triggering the toxic events that lead to progressive neurodegeneration. However, no drug candidate targeting the cascade has yet pro- duced a successful treatment. It is now speculated that treatment requires early targeting of Aβ, when pathology remains reversible, and clinical trials are focusing on assessing Aβ compounds in pro-dromal AD. Lack of an effective A β-focused treat- ment has resulted in the consideration of hyperphosphorylated neurofibrillary tangles of tau (NFT), another major pathologi - cal hallmark of AD. Studies have repeatedly demonstrated a strong correlation between NFT build up and cognitive decline, and recent studies have identified a number of tau genetic markers associated with AD. Compounds preventing the hyper - phosphorylation of tau may therefore halt disease progression; however, the failure of previous tauopathy trials in progres- sive supranuclear palsy (PSP) has highlighted potential set-backs. The importance of tau as an independent cause of AD, and therefore a target for treatment, may be clarified by ongoing tau-focused clinical studies. Although A β and tau are both highly relevant, their relationship in causing AD remains unknown. Amyloid- and tau-targeting treatments may individually prove effective, however the convergent progression of A β and tau pathology suggests combination therapy may eventually be required, particularly in late stages of disease when both are abundant. While ongoing work focuses on single target thera- pies, a dual Aβ and tau targeting approach may be more likely to produce a breakthrough. Key words: Alzheimer’s disease (AD), amyloid beta (Aβ), tau, neurodegeneration, tauopathy, dementia Submitted on 20 November 2013; accepted on 12 May 2014 Introduction causing the brains of patients to weigh up to one-third less than that of an age-matched non-demented individual Alzheimer’s disease (AD) is an age-related, neurodegenerative (Laferla, Green and Oddo, 2007). AD is the most common disorder characterized by progressive neuronal loss in areas cause of dementia, accounting for approximately 60–80% of of the brain associated with cognitive learning and memory. all cases (AD Facts and Figures, 2010). It is estimated that AD occurs due to a combination of pathological changes in 35.6 million people worldwide suffer from dementia, with the brain which result in severe neuronal and synaptic loss, numbers expected to double every 20 years (Prince et al., © The Author 2014. 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/3.0/), 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  Review Bioscience Horizons • Volume 7 2014 2013; WHO, 2012). As well as the substantial personal cost, the hypothesis that the Amyloid Cascade is an insufficient tar - the total estimated worldwide financial burden of dementia get for the treatment of AD, and development of a potential was $604 billion in 2010 (Wimo et al., 2013). cure must consider both amyloid and tau pathology together. Extracellular amyloid beta (Aβ) aggregates, and intracel- lular hyperphosphorylated neurofibrillary tangles (NFT) of The Amyloid Cascade Hypothesis tau, constitute the two major pathological hallmarks of AD The Amyloid Cascade Hypothesis identifies A β aggregation (reviewed by Finder, 2010). These characteristic pathologies or decreased Aβ clearance as a trigger of the toxic events lead- have resulted in the proposal of two theories regarding the ing to substantial neurodegeneration (Hardy and Higgins, cause of AD. The Amyloid Cascade Hypothesis identifies 1992; Hardy and Selkoe, 2002). Aβ is generated through the increased Aβ aggregation or decreased Aβ clearance as the proteolytic processing of the type 1 integral membrane glyco- primary cause of disease, developing years prior to clinical protein, amyloid precursor protein (APP) (Finder, 2010). APP onset (Hardy and Higgins, 1992; Hardy and Selkoe, 2002). was identified in 1987 ( Kang et al., 1987) and duplication of Accumulation of pathogenic Aβ peptide species and insoluble the APP locus was subsequently reported to cause autosomal- plaque formation is believed to trigger a number of detrimen- dominant early-onset AD and cerebral amyloid angiopathy tal processes, including hyperphosphorylation of tau, which (CAA) (Rovelet-Lecrux et al., 2006). Processing of APP to Aβ lead to neuronal death (reviewed by Pimplikar, 2009). The occurs via one of the two major pathways, the amyloidogenic Tau Hypothesis is based on evidence that tau tangle pathology pathway and the non-amyloidogenic pathway, through cleav- occurs prior to Aβ plaque formation and more closely corre- age by a group of enzymes called alpha (α), beta (β) and lates with disease progression and severity than Aβ plaque gamma (γ) secretases. It is now widely accepted that Aβ occurs load (Braak and Braak, 1991). Although the mechanism by in two predominant forms, Aβ1-40 and Aβ1-42, sharing a which Aβ and tau interact remains uncertain (Ittner and Gotz, common N-terminus but differing in their carboxy-termini 2011), evidence has implicated both to be causative of AD. (Younkin, 1998; Jankowsky et al., 2004). AD results in a spectrum of symptoms including mild cogni- Under normal, non-pathological circumstances, the non- tive impairment, deficits in short-term and spatial memory, amyloidogenic pathway predominates, resulting in the cleav- emotional imbalances, loss of executive functions and progres- age of APP by α-γ-secretases. This pathway precludes sive dementia (reviewed by Pimplikar, 2009; Singh et al., deposition of intact Aβ peptide by producing a smaller, less 2012). The disease can be divided into two main categories, amyloidogenic form of Aβ only 40 residues in length (Aβ1- sporadic late-onset AD (LOAD) and early-onset familial AD 40), which is less likely to aggregate and cause toxicity (Jarrett, (FAD) (Finder, 2010). FAD accounts for less than 1% of all Berger and Lansbury, 1993). Under pathogenic circumstances, cases (AD Facts and Figures, 2010), with onset occurring APP is cleaved by β-γ-secretases to produce the more amy- between the ages of 55 and 65 due to genetic predisposition loidogenic Aβ1-42, the major species detected in the brains of (Bird, 1999). Although uncommon, mutations identified to AD patients (Iwatsubo, 1998; Finder and Glockshuber, 2007). cause FAD have provided important insights into the potential Overproduction of Aβ1-42 has been reported to cause FAD causes of sporadic AD, for which the greatest risk factor is age- and is speculated to be a cause of sporadic AD (Younkin, ing (Finder, 2010). FAD mutations implicated Aβ as a primary 1998). Aβ1-42 is considered pathogenic due to its greater cause of disease, resulting in the Amyloid Cascade Hypothesis hydrophobicity and longer length of 42 residues (Jarrett, becoming the dominant focus of research. However, failure to Berger and Lansbury, 1993). develop an Aβ targeting compound into a successful treatment for AD has cast doubt upon its relevance, resulting in the Tau Processing of APP by γ-secretase activity constitutes the Hypothesis re-surfacing. There are currently a number of final step in the release of both A β1-40 and Aβ1-42 (Herreman ongoing clinical trials assessing the ability of tau inhibitors to et al., 2000). Two genes, Presenilin 1 (PSEN1) and Presenilin reduce AD progression (ClinicalTrials.gov Identifiers: 2 (PSEN2), encode for the proteins presenilin 1 (PS1) and NCT01689233 and NCT01689246). Definitive conclusions presenilin 2 (PS2), respectively, both of which contribute to regarding the relevance of these tau-based drug candidates lie the secretase complex. Mutations in these genes have been with the completion and publication of clinical trial results. identified as being correlative of AD ( Younkin, 1998). Despite substantial efforts in drug development and an increased understanding of the underlying pathology of AD, The Tau Hypothesis no effective treatment has yet been identified. All currently The Tau Hypothesis identifies tau hyperphosphorylation as an approved drugs target symptoms and improve quality of life independent and primary cause of AD, due to observations that rather than modify disease progression. These treatments have tau tangle pathology occurs prior to Aβ plaque formation and relatively short-term, limited benefits ( Takeda et al., 2006; that NFT load more closely correlates with disease progression Raina et al., 2008) and emphasize the urgent need to continue and severity than plaque load (Braak and Braak, 1991). Alois the research efforts. Repeated failures to develop an effective, Alzheimer first reported his findings of NFT in 1907 ( Alzheimer, disease-modifying therapeutic, suggests the need to re-think 1907), and a correlation between tangle formation and the current approach to AD treatment. This review considers 2 Bioscience Horizons • Volume 7 2014 Review Alzheimer’s dementia was identified in 1968 ( Blessed, Tomlinson Genetics and Roth, 1968). The structure and composition of these char- Supporting evidence for the Amyloid Cascade Hypothesis acteristic tangles were not established until 1988 (Goedert et al., was provided by the mapping of several Aβ-increasing FAD 1988). In AD brains, hyperphosphorylated tau is the major mutations to the APP gene (Owen et al., 1990) and the pre- component of both NFTs in pyramidal neurons, and neuropil disposition of Down’s syndrome patients to AD due to ele- threads in distal dendrites (Finder, 2010). NFTs are filamentous vated lifetime APP production (Glenner and Wong, 1984; inclusions of tau which occur both in AD and in other tauopa- Rovelet-Lecrux et al., 2006). thies (Lee, Goedert and Trojanowski, 2001; Querfurth and LaFerla, 2010). Under normal conditions, tau is a soluble, abun- Studies have identified over-expression of APP, and subse - dant protein found in axons, which maintains assembly and quent generation of the Aβ1-42 peptide, to be central to neu- stability of microtubules and vesicular transport (Finder, 2010; ronal degeneration observed in AD (Skaper, 2012). Down’s Querfurth and LaFerla, 2010). Microtubule-associated tau pro- syndrome patients present with elevated APP, due to triplica- tein has been reported to be critical for normal neuronal activity tion of chromosome 21 (the location of the APP gene), and in the mammalian brain (Iqbal et al., 2005). develop increased Aβ accumulation in early life (Singh et al., 2012). Such patients often develop AD in their 30s, suggest- Phosphorylation and dephosphorylation of tau is regu- ing that increasing Aβ production predisposes individuals to lated by various kinases and phosphatases that add or remove AD (Singh et al., 2012). phosphate residues, respectively (Iqbal et al., 2005; Querfurth and LaFerla, 2010). Under pathological conditions, such as FAD, which typically manifests with an early-onset patho- AD and other tauopathies (Lee, Goedert and Trojanowski, genesis (Laferla, Green and Oddo, 2007), is characterized by 2001), hyperphosphorylation of tau results from both an similar Aβ pathology to sporadic AD, providing insights into imbalance in tau kinase and phosphatase activity and changes the possible causes of disease. A number of mutations, includ- in tau’s conformation (Iqbal et al., 2005). These changes ren- ing 32 APP missense mutations, over 150 PS1 mutations and der tau protein insoluble and reduce its affinity for microtu - 20 PS2 mutations, have been identified as correlative of AD bules, causing it to detach and spontaneously self-associate (Pimplikar, 2009; Finder, 2010). These mutations result in into paired helical filament structures ( Querfurth and either elevated production of total Aβ or a specific increase in LaFerla, 2010). These filaments then aggregate into NFTs, the levels of Aβ1-42, (Citron et al., 1992; Cai, Golde and disturbing and impairing axonal transport (Finder, 2010). Younkin, 1993; Bekris et al., 2010). Interestingly, protective Toxic forms of tau protein eventually ‘choke’ the neurone by mutations such as the A673T variant of APP, result in a 20% preventing the possibility of normal neuronal metabolism reduction in lifelong production of Aβ and prevent individu- and causing progressive neurodegeneration (Iqbal et al., als from developing cognitive impairments and AD (Jonsson 2005; Wischik et al., 2010). The resulting toxicity eventually et al., 2012). Therefore, mutations that increase Aβ produc- leaves behind only a marker of a previously existing neurone, tion predispose individuals to AD, whereas those that referred to as a ‘ghost’ tangle (Wischik et al., 2010). decrease Aβ appear protective. However, some PS1 muta- tions promote neurodegeneration and frontotemporal The amyloid hypothesis fails to dementia (FTD) without causing an increase in Aβ plaque explain all aspects of AD; evidence pathology or altering the Aβ40 to 42 ratio (Shioi et al., suggests tau may fill the gaps 2007), suggesting that their ability to cause neuronal toxicity in AD may be distinct from their effects on Aβ production. Studies have provided a wealth of supporting evidence for the Furthermore, no correlation between increased Aβ42, induced Amyloid Cascade Hypothesis, emphasizing Aβ to be a pri- by FAD mutants and age of disease onset was reported mary cause of AD. However, the pathogenic nature of Aβ has (Scheuner et al., 1996). Therefore, although some studies become increasingly questioned due to evidence reporting the provide strong evidence for the involvement of APP, PS1 and presence of Aβ plaques in healthy individuals, the lack of a PS2 in AD, they do not identify Aβ is the single primary cause defined pathogenic A β species and the repeated clinical fail- of disease. Indeed, reports of neuronal dysfunction via path- ures of Aβ targeting drug candidates (reviewed by Pimplikar, ways independent of APP and Aβ (Shioi et al. 2007; Baki 2009). Recent research suggests that NFT formation occurs et al., 2008) have reduced the focus on Aβ as the causative early and is a primary cause of toxicity (Wischik et al., 2010), agent of AD (Caughey and Lansbury, 2003, reviewed by whilst Aβ plaque formation may be a late-stage, neuroprotec- Pimplikar, 2009). tive event (reviewed by Maccioni et al., 2010). The theory that tau is an independent cause of AD is strengthened by Understanding the genetic basis of tau pathology in AD is observations that tau oligomers are directly toxic to neurons advancing rapidly. Initial evidence linking tau tangle forma- and tau pathology correlates with clinical cognitive decline in tion to neurodegeneration was provided by other tauopa- AD (Wischik et al., 2010). Tau hyperphosphorylation may be thies, displaying characteristics similar to AD. Tauopathies a convergent point of toxicity in the AD brain (Maccioni encompass a number of disorders, all of which result from et al., 2010), highlighting the potential for tau-targeting ther- the accumulation of abnormally hyperphosphorylated tau apeutics in clinical AD. and are associated with NFT formation and dementia (Iqbal 3 Review Bioscience Horizons • Volume 7 2014 et al., 2005). Over 30 mutations found on chromosome 17 the ERC, demonstrated a subsequent spreading of pathology (the location of the gene which encodes for tau, MAPT) are with ageing to regions of the brain innervated by ERC neu- associated with FTD and parkinsonism, supporting dysfunc- rons, particularly the hippocampus which is greatly affected tional tau protein as a primary cause of neurodegenerative in the later stages of AD (Liu et al., 2012). The spreading of disease (Goedert and Jakes, 2005). Identified mutations in tau pathology was found to be consistent with that seen upon MAPT reduce the ability of tau protein to interact with post-mortem examination of human AD brains (Liu et al., microtubules and increase its tendency to assemble into 2012). These findings suggest that tau-targeting treatments abnormal filaments ( Goedert and Jakes, 2005), consistent designed to inhibit the spreading of pathology in the early with tau pathology in sporadic AD. A recent genome-wide stages may have the potential to halt disease progression. association study found genetic markers associated with ele- vated levels of tau and phosphorylated tau in the cerebrospi- Animal models and clinical trials nal fluid of AD patients ( Cruchaga et al., 2013). Research led Identifying FAD mutations allowed AD to be modelled in by Dr. Alison Goate yielded particular genetic signals linked animals, although their usefulness remains controversial due to enhanced tau pathology in the brain and a faster rate of to the repeated failure of drugs effective in animal models to cognitive decline (Cruchaga et al., 2013). Although addi- treat AD in humans. Currently used animal models have been tional research is required to identify where these candidate developed using mutated APP, PS1 and MAPT genes, com- genes are expressed and whether more may be associated monly APP , PS1 and MAPT (Oddo et al., 2003). with tau-related pathology, the results highlight the possibil- Swe M146V P301L These models develop plaques and tangles in an age- ity of novel therapeutic targets or alternative models of AD. dependent manner and closely represent human AD (Oddo In addition, the findings demonstrate the ability of tau et al., 2003; 2006; Filali et al., 2012). Importantly, mice pathology to cause AD independently of Aβ pathology. expressing a combination of mutant APP, PS1 and MAPT Pathophysiology genes display plaques and tangles, and a reduction of both Aβ and tau is required to ameliorate cognitive decline (Oddo The Amyloid Cascade Hypothesis fails to explain the poor et al., 2006). Aβ reduction alone failed to demonstrate correlation between plaque load and the degree of dementia improvement in the cognitive phenotype in both spatial and in humans (Terry et al., 1991). Although one study identified contextual learning and memory paradigms, highlighting the a correlation between cognitive dysfunction and Aβ plaque potential role of tau in cognitive decline in the presence of formation in the entorhinal cortex (ERC) (Cummings et al., concomitant Aβ pathology (Oddo et al., 2006). 1996), many have reported a weak and inconsistent, if any, relationship between Aβ pathology and cognitive decline As of May 2014, all Aβ-targeting treatments have failed to (Crystal et al., 1988; Arriagada et al., 1992). It was reported generate significant improvements when trialled in the clinic, by Crystal et al. (1988) that cortical senile plaque count did according to the ClinicalTrials.gov database (Table 1). Anti- not distinguish between demented and non-demented indi- amyloid immunotherapy became the focus of Aβ-targeting viduals. This was supported by reports of non-demented indi- research, following the finding that anti-amyloid monoclonal viduals presenting with significant plaque load upon autopsy antibodies dissolved Aβ aggregates and prevented their for- (Wischik et al., 2010). Live molecular imaging techniques mation in vitro (Solomon et al., 1996). However, Aβ immu- have since confirmed the presence of plaques in the brains’ of notherapy has been faced with a number of safety and efficacy cognitively normal individuals in vivo (Nordberg, 2008; drawbacks, including encephalitis, a lack of clinical improve- Villemagne et al., 2008). These findings suggest that plaques ment and an absence of effect on NFTs (Rosenmann, 2013). are not necessarily causative of memory deficits, indicating As a central role of NFTs in dementia is becoming more flaws in the Amyloid Cascade Hypothesis. Importantly, the apparent, it is likely that clearance of amyloid pathology is lack of correlation between plaque load and cognition has insufficient to improve dementia symptoms in AD patients. likely influenced the clinical failure of many A β-targeting ther- Indeed, although amyloid pathology has often been found to apeutics. However, recent data have suggested that the species be upstream of tau pathology, amyloid-toxicity has been of Aβ is important for toxicity, and that Aβ plaques may con- reported to be tau-dependent, highlighting the potential for stitute a less toxic aggregate (reviewed by Pimplikar, 2009). tau-targeting therapies to prevent both pathologies The exact role of Aβ in AD therefore remains unknown. (Rosenmann, 2013). Conversely, tau aggregation and the resultant brain lesions The failure of anti-amyloid trials has triggered discussions observed in AD have been repeatedly reported to correlate assessing the cause of drug candidate failure. Importantly, with clinical dementia and cell death (Iqbal et al., 2005; recent Phase III trials of bapineuzumab and solanezumab Wischik et al., 2010). Hyperphosphorylated tau is reported reported that approximately 25% of study patients diagnosed to spread in a clearly defined sequence, mapping clinically to with mild AD had negative positron emission tomography measurable stages of cognitive decline and physically to (PET) Aβ imaging (Karran & Hardy, 2014). As these patients stages of loss of brain function seen in AD patients (Braak lack Aβ pathology, they are unlikely to benefit from anti- and Braak, 1991; Braak et al., 2011). Transgenic mice amyloid treatments, therefore impacting the overall efficacy expressing human mutant MAPT predominantly in layer 2 of outcome of the study. In addition, many argue that the 4 Bioscience Horizons • Volume 7 2014 Review targeted patient population often presented with abundant treatment. Importantly, previous anti-amyloid trials (Table 1) and irreversible Aβ pathology at the time of the trials (Karran, have tested several compounds, each with distinct mechanisms Mercken and De Strooper, 2011). Karran, Mercken and De of action. It is therefore probable that different stages of the Strooper (2011) proposed an Aβ trigger scenario explaining disease process and various forms of Aβ have already been AD progression. They suggested that during disease progres- targeted, further emphasizing the failure of this approach. sion an Aβ deposition threshold is eventually reached, whereby Targeting Aβ alone at clinically relevant stages of AD, when there is sufficient ‘aggregate stress’ to initiate or accelerate Aβ and tau pathology are abundant, has so far appeared insuf- tau pathology, which then becomes self-sustaining and ficient to successfully treat the disease, probably due to its Aβ-independent. At this point, therapeutic intervention cannot highly complex, multi-factorial pathology. Ongoing be effective. Interest in this theory has initiated clinical trials preventative anti-amyloid investigations, including the testing individuals with early signs of dementia, termed pro- Dominantly Inherited Alzheimer’s Network (DIAN), dromal AD, who are considered at risk of developing AD Alzheimer’s Prevention Initiative (API) and Anti-Amyloid (Karran, Mercken and De Strooper, 2011). These trials present treatment in Asymptomatic Alzheimer’s Disease (A4) trials a huge clinical challenge, particularly regarding the selection (Carrillo et al., 2013), will provide further insights into early of the clinical trial population and ethical considerations. AD development and progression, and may answer the long- F. Hoffmann-La Roche Ltd. is currently assessing a monoclo- standing questions regarding the Amyloid Hypothesis. nal antibody that recognizes Aβ, gantenerumab, in patients within the prodromal phase (Ostrowitzki et al., 2012). The Tau-based drug discovery is advancing rapidly, although mechanism by which anti-amyloid antibodies remove Aβ from limited focus on tau in previous years has hindered the pro- the brain is speculated to be via effector cell-mediated phago- gression of such therapeutics to Phase III trials. A number of cytosis or direct dissolution of amyloid (Weiner and Frenkel, inhibitors of tau aggregation have already been identified, 2006). Gantenerumab is reported to cause Fc receptor/ with three distinct mechanisms of action (reviewed by microglia-mediated phagocytosis of amyloid, followed by Brunden, Trojanowski and Lee, 2009). Tau-based research lysosomal degradation (Bohrmann et al., 2012). If unsuccess- has focused primarily on compounds that either inhibit the ful in Phase III, this trial will suggest past failures are not due kinases responsible for phosphorylation of tau or inhibit to administration of Aβ-therapeutics too late in disease pro- the aggregation of tau. Compounds preventing the disasso- gression, confirming flaws in the A β-focused approach to AD ciation of tau from microtubules have also been investigated, Table 1. Progress of late-phase clinical trials targeting the Amyloid Cascade Hypothesis Drug type Drug name Phase Reason for failure Aβ aggregation Alzhemed™ Results obtained could not support a claim for clinical efficacy (ClinicalTrials.gov Identifier: III inhibitor (Tramiprosate) NCT00088673) Evaluated in two Phase III trials, the Interrupting Alzheimer’s dementia by evaluating treatment of amyloid pathology (IDENTITY ) trial and the IDENTITY-2 trial (ClinicalTrials.gov γ-Secretase identifier: NCT00594568 and NTC00762411). Patients receiving Semagacestat displayed an Semagacestat III Inhibitor increased deterioration in cognition and activities of daily living compared to placebo- treated controls. Semagacestat was also found to be associated with an increased risk of skin cancer compared to placebo (Karran, Mercken and De Strooper, 2011) γ-Secretase Flurizan™ No statistically significant effect in co-primary outcome measures of cognition and activities III modulators (tarenflurbil) of daily living was observed (ClinicalTrials.gov Identifier: NCT00105547) Safety findings were reported, including the development of aseptic meningoencephalitis Aβ active AN1792 III and leukoencephalopathy in 6% of vaccinated patients (ClinicalTrials.gov Identifier: immunotherapy NCT00021723) No significant efficacy found. Furthermore, vasogenic oedema was reported during the study, Aβ passive Bapineuzumab III particularly in ApoE4 carriers. Due to these safety findings, the highest dose was discontinued immunotherapy (ClinicalTrials.gov Identifier: NCT00575055 and NCT00574132; Salloway et al., 2014) Failed to reach its cognitive or functional endpoints in either of two double-blind, placebo- controlled trials in patients with mild to moderate Alzheimer’s disease EXPEDITION and Solanezumab III EXPEDITION-2 (ClinicalTrials.gov Identifier: NCT00905372 and NCT00904683, Siemers et al., 2010), despite acute and sub-chronic treatment attenuating or reversing memory deficits in transgenic mice (Imbimbo et al., 2012) Gantenerumab II/III Ongoing (Clinical Trials.gov identified NCT01224106, NCT02051608 and NCT01760005) Numerous failures and discontinuations have highlighted possible inconsistencies in the Amyloid Hypothesis. (Information from ClinicalTrials. gov, Alzforum.org, Rosenmann, 2013). 5 Review Bioscience Horizons • Volume 7 2014 although to a lesser extent (reviewed by Boutajangout by accumulating evidence from anti-tau immunotherapy, et al., 2011; Zhang et al., 2012). Glycogen synthase kinase demonstrated to effectively reduce tau-pathology and 3β (GSK3β), cyclin dependant kinase 5 (CdK5) and improve the symptoms of dementia in animal models, includ- microtubule-affinity-regulating kinase (MARK) have been ing motor function and cognitive decline (reviewed by reported to collectively represent the three major tau kinases Rosenmann, 2013). As tau-based drug development is some responsible for phosphorylation of tau (reviewed by 20 years behind Aβ, the advancement of current pre-clinical Geschwind, 2003; Chung, 2009). Substantial pre-clinical tau-targeting compounds to the clinic is highly anticipated work has demonstrated that GSK3 and CdK5 inhibitors can and may prove extremely informative. prevent tau hyperphosphorylation (reviewed by Bhat et al., 2008; Boutajangout, Sigurdsson and Krishnamurthy, 2011). Tau and amyloid interact to cause Tau-based immunotherapy has also emerged as a potential disease approach for reducing both Aβ and tau pathology and has been explored in animal studies (reviewed by Rosenmann, The relationship between Aβ and tau in AD pathogenesis 2013). Some of the most advanced tau-based therapeutics remains controversial. Although drug development has often being evaluated in the clinic are the tau aggregation inhibi- focused on targeting Aβ and tau pathology in isolation, both tors. Rember recently became the first tau-aggregation may require targeting for effective disease-modifying treat- inhibitor to be clinically investigated by TauRx , a company ment. Continued research into their interplay will provide dedicated to tau-based therapeutics (taurx.com). TauRx alternative methods for intervention. Current evidence from reported success in completed Phase II trials assessing in vitro and in vivo models suggests three possible mecha- Rember (ClinicalTrials.gov Identifier: NCT00515333) and nisms by which they interact (Fig. 1). subsequently initiated two ongoing Phase III trials assessing the second-generation drug LMTX™ (ClinicalTrials.gov Aβ is causative of some tau pathology Identifier: NCT01689233 and NCT01689246). However, lack of published data regarding the completed Phase II tri- Several studies have provided evidence that tau tangles can be als, along with the current absence of any additional conclu- induced by Aβ. Ferrari et al. (2003) reported that exposure to sive Phase III trials, highlights the need to be cautious when Aβ was sufficient to induce tau filament formation in a human considering the potential of tau-based therapeutics. tissue culture system, in the absence of mutations in tau Furthermore, the Allon small peptide davunetide, developed (Ferrari et al., 2003). Furthermore, mice with mutations in the to target tau pathology, failed to meet its primary and sec- genes encoding APP and tau displayed a sevenfold increase in ondary endpoints when evaluated in a Phase II/III study in NFTs, compared with mice with mutations only in the tau PSP (ClinicalTrials.gov Identifier: NCT01110720). Similarly, gene (Lewis et al., 2001). In the same study, Aβ plaque forma- tideglusib, a GSK-3 inhibitor developed by Noscira, failed to tion was unaffected by the presence of tau lesions (Lewis meet its co-primary endpoints in two separate Phase II stud- et al., 2001). Similarly, intracranial injection of Aβ42 fibrils ies in PSP and AD (del Ser et al., 2013; Tolosa et al., into mutant tau transgenic mice caused a fivefold increase in 2014; ClinicalTrials.gov Identifier: NCT01049399 and NCT01350362). However, tideglusib was reported to reduce global brain atrophy compared with placebo in the PSP study, with the largest effect seen in the parietal and occipital lobes, indicating a possible neuroprotective effect (Höglinger et al., 2014). Importantly, these brain areas are only minimally impacted in PSP, providing an explanation for the lack of clinical outcome in this population (Höglinger et al., 2014). The pilot study of tideglusib in AD reported trends towards cognitive improvement, although these failed to reach sta- tistical significance due to the small sample size ( del Ser et al., 2013). As tideglusib has been reported to target the frontal lobe and hippocampus, the potential of GSK-3 inhibitors in AD should be further explored (Höglinger et al., 2014). Tau-based therapeutics may still represent the first major breakthrough in disease-modifying treatment for AD; how- ever, such claims have yet to be supported by successful Phase Figure 1. Progression of AD pathology. Flow chart to depict the toxic III trials. Unlike Aβ-targeting therapeutics, targeting tau pathways reported to lead to development of AD. Whether Aβ is pathology may hold the potential to delay cognitive decline causative of tau pathology or vice versa is currently unknown. It at later stages in disease progression, when Aβ and tau appears likely that both eventually promote a pathway of neuronal pathology are present. This has been particularly supported degeneration, leading to progressive dementia and death. 6 Bioscience Horizons • Volume 7 2014 Review NFT pathology as early as 18 days post injection (Gotz et al., the significance of this claim (reviewed by Pimplikar, 2009). It 2001). This increase in AD-like tau pathology suggests that is now accepted that Aβ oligomers may be a more toxic form Aβ may be toxic via acceleration of tau hyperphosphoryla- of protein aggregation, with plaques being less relevant to dis- tion, supporting the theory that compounds targeting Aβ may ease progression, although research aimed at reducing Aβ be sufficient to treat AD by preventing tau pathology. plaques is still ongoing (ClinicalTrials.gov). However, at later stages in disease progression, when hyper- Aβ and Tau demonstrate synergistic effects phosphorylated tau is self-sustaining, Aβ-targeting therapeu- tics have proven ineffective. Importantly, tau aggregates can It has been suggested that tau and Aβ interact by targeting form in the absence of Aβ pathology, for example in FTD, different components of the same system to amplify each where mutations in tau-encoded MAPT genes result in the other’s toxic effects downstream (reviewed by Ittner and hyperphosphorylation of tau (Ballatore, Lee and Trojanowski, Gotz, 2011). An example of such synergistic effects is the 2007). However, it is possible that while mutant tau may cir- implication of both Aβ and tau in the impairment of cumvent the need for Aβ-induction of hyperphosphorylation, mitochondrial proteins related to complexes I and IV of wild-type tau may still require Aβ to trigger tangle formation. the oxidative phosphorylation system, in mice expressing It may also be argued that although diseases such as FTD pro- APP PS2 MAPT which display both Aβ and tau Swe N141I P301L vide important insights into tau-based pathology in AD, they pathology (Rhein et al., 2009). It was found that deregula- remain distinct from AD in their symptomatology and pathol- tion of complex I was tau-dependent, whereas deregulation ogy. Regardless, the observation that tau pathology can occur of complex IV was Aβ dependent, both at the protein and in the absence of prior Aβ pathology has enhanced research activity levels (Rhein et al., 2009). Therefore, by acting on into tau toxicity in isolation, building supportive evidence for the same system, tau and Aβ may enhance the downstream the theory that tau develops early and acts as a primary and toxic events related to AD. Although the mechanism of Aβ independent cause of AD. and tau interplay remains largely unknown, this provides evi- dence for a molecular link between the proteins and AD Tau is required for neurodegeneration pathology. It appears almost certain that they interact to and Aβ pathology either cause or enhance the progression of AD. Therefore, although no proof of concept is currently available, a com- With many Phase II and III clinical trials targeting Aβ failing bined therapy targeting both pathologies may eventually con- to produce a marketed treatment for AD (ClinicalTrials.gov), stitute the most effective approach to treatment. the view that tau is a secondary effect of Aβ pathology is becoming less favourable. Rapoport et al. (2002) reported that tau-depleted neurons showed no signs of degeneration in Conclusion the presence of Aβ, providing direct evidence to support an essential role for tau in the Aβ-mediated toxicity and neuro- As proof of a single dominant underlying cause of AD degeneration seen in AD (Rapoport et al., 2002). Furthermore, remains inconclusive, it is logical to accept that both tau and Ittner et al. (2010) reported that tau reduction blocked Aβ Aβ pathologies are highly influential. Considering this state - and excitotoxin-induced neuronal dysfunction. Although tau ment, a disease-modifying therapeutic must target both is predominantly found in axons, it is thought to have an pathological hallmarks. A range of drug candidates targeting important dendritic role that confers Aβ toxicity at the post Aβ alone have now been assessed, all of which have reported synapse through targeting of the Src Kinase FYN, a substrate limited success in clinical trials. Of these, immunotherapy of which is the NMDA receptor (Lee et al., 1998). Tau there- appears to most effectively target Aβ deposits in the brain, fore may be involved in the early-phases of AD, in contrast to despite failing to reduce cognitive decline. Supporters of the the widely accepted theory that tau is secondary to Aβ toxic- Amyloid Cascade Hypothesis have therefore emphasized the ity. Transgenic mice expressing truncated tau (tTau) or defi - potential of immunotherapy to treat early AD, before Aβ −/− cient in tau (Tau ) showed disruptions in postsynaptic pathology becomes irreversible (Karran, Mercken and De targeting to FYN, arresting Aβ-mediated excitotoxicity by Strooper, 2011). Indeed, observations of Aβ pathology in reducing interactions of NMDA receptors with postsynaptic years prior to clinical onset of dementia warrant continued density protein 95 (PSD95) (Ittner et al., 2010). Excitotoxicity clinical trials assessing Aβ-targeting therapeutics in prodro- is increasingly accepted as the mechanism by which Aβ exerts mal AD. Such ongoing trials will provide a definitive answer toxicity and, by blocking this mechanism using mice deficient regarding the relevance of treatment approaches targeting in tau or expressing truncated tau, memory deficits were pre - the Amyloid Hypothesis. Previous research has implicated vented and survival was improved (Ittner et al., 2010). Aβ as one of the major contributing factors rather than the Tau-initiated Aβ toxicity is further supported by the observa- sole cause of disease. Substantial research now implicates tion that NFT formation predates plaque formation (Braak hyperphosphorylated tau an independent cause of AD, et al., 1996), suggesting tau pathology may be present prior to and tau inhibitors are currently being investigated in clini- Aβ pathology. However, more recent research has suggested cal trials (ClinicalTrials.gov Identifier: NCT01689233 and that only certain forms of Aβ are inducers of tau pathology NCT01689246). Due to the current lack of published data and that Aβ plaques are a late-stage Aβ species, diminishing regarding these drug candidates, it remains premature to 7 Review Bioscience Horizons • Volume 7 2014 phosphatidylinositol 3-kinase neuroprotective signaling, The suggest that tau-based treatments will provide a cure for AD. Journal of Neuroscience, 28, 483–90. The outcome of the ongoing Phase III trials investigating tau inhibitors, along with continued research into tau genetic Ballatore, C., Lee, V. M. and Trojanowski, J. Q. 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Journal

Bioscience HorizonsOxford University Press

Published: Jun 17, 2014

Keywords: Alzheimer's disease (AD) amyloid beta (Aβ) tau neurodegeneration tauopathy dementia

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