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Stem cells slow cognitive decline in Alzheimer's disease via neurotrophin action

Stem cells slow cognitive decline in Alzheimer's disease via neurotrophin action BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu013 Review Stem cells slow cognitive decline in Alzheimer’s disease via neurotrophin action Rose Mulvey* Imperial College London, Charing Cross Campus, Fulham Palace Road, London W6 8RF, England *Corresponding author: 39 Epirus Road, London SW6 7UR, England. Email: rose.mulvey09@imperial.ac.uk Supervisor: Dr Jane Saffell 411 Burlington Danes, Hammersmith Campus, Du Cane Road, London W12 0NN, England. Email: j.saffell@impeiral.ac.uk Alzheimer’s disease is a growing concern with no satisfactory current treatment solution. Contemporary stem cell research offers a new arena for development in this field. Transplantation of stem cells into the damaged brain brings hope of repair to damaged neurons. This appears to operate via a ‘bystander effect’ whereby neurotrophins secreted by the cells act as a neuro - protectant, rather than a cell replacement mechanism as some have postulated. Such treatments can slow or even reverse cognitive decline. Research into neural stem cell transplantation has shown reversal of cognitive decline in animal models of disease via the mechanism of brain-derived neurotrophic factor secretion. Studies using nerve growth factor secreting stem cells have showed promising results with cognitive decline reversed in animal models of the disease. A Phase 1 clinical trial also showed promising reversal of cognitive decline in human subjects using transplantation of nerve growth factor secreting fibroblasts. Mesenchymal stem cells have also shown promise, and results from human trials are awaited. Induced pluripotent stem cells have provided a successful model of human disease in vitro. Although early results from transplant studies are encouraging, a lot more research will be needed before these preliminary advances can be translated to therapies with a strong evidence base to be used in practice. Key words: Alzheimer’s, stem cells, transplantation, BDNF, NGF, cognitive decline Submitted on 3 April 2014; accepted on 4 December 2014 Alzheimer’s disease is the most common form of dementia. patients who need long-term care solutions. Additionally, and There is no cure, and current treatments are palliative and arguably more importantly, Alzheimer’s puts a huge emo- offer a symptomatic relief of a limited duration. Pathologically, tional burden on caregivers and family members, who are the brain suffers from loss of neurons and decreased numbers forced to watch loved ones slowly lose their abilities and per- of synapses, with a build-up of plaques of amyloid-beta pro- sonalities. With an estimated one in two people over the age tein and fibrillary tangles of tau protein, leading to disruption of 85 set to suffer from the disease (Zhu and Sano, 2006), this of normal function and eventually cell death. This occurs in predicament may be all too close to home for many of us. specific areas of the brain including the hippocampus, basal Currently, NICE recommend only four treatments for forebrain cholinergic neurons and areas of the cortex that are Alzheimer’s. Three of the four: donezipil, rivastigmine and involved in learning and memory. The disease manifests in galantamine are acetylcholinesterase inhibitors. These prolong problems of memory and learning, and general cognitive the presence of acetylcholine (a neurotransmitter involved in decline that worsens over time. memory function) at the synapse, by blocking the enzyme With the number of sufferers set to rise to 42.2 million acetylcholinesterase. This slows deterioration of cognitive worldwide by 2020 and 81.1 million by 2040 (Ferri et al., function in patients with mild to moderate disease (Wolfson 2005), this clearly poses a great problem for healthcare pro- et al., 2002; Birks, 2006; Prvulovic and Schneider, 2014). The viders, not least one of funding to support large numbers of fourth, memantine is an NMDA receptor antagonist. It p revents © 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/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  Review Bioscience Horizons • Volume 7 2014 excitatory glutamate neurotoxicity (Choi, 1992) and has been 2013). For example, neural stem cells (NSCs) can differentiate shown to be effective in severe dementia (Di Santo et al., into neurons, astrocytes or oligodendrocytes (Taupin, 2006). 2013). With these treatments only able to slow cognitive In adults, NSCs are found in the subgranular zone and decline for a period, before allowing the disease to resume its subventricular zone of the hippocampus (Taupin, 2006), part course, there is real need for disease modifying therapies that of the brain which is important for learning and memory could halt cognitive decline or even reverse its course. A poten- (Deng, Aimone and Gage, 2010). tial new drug, Dimebon, an antihistamine, recently showed promise in early trials (Doody et al., 2008), but then it failed in NSCs express high levels of neurotrophins including BDNF Phase III clinical trials (Miller, 2010). It would seem that a new and NGF (Lu et al., 2003; Kamei et al., 2007). Transplantation approach to the problem is needed. of these cells into areas of pathology in the brain would there- fore present a mechanism of delivery of these factors directly to the brain which avoids the difficulty of the factors being Neurotrophin activity unable to cross the blood–brain barrier, a problem intrinsic to Research has shown that despite the obvious pathological hall- more peripheral methods of delivery. A stem cell graft would marks of protein plaques and fibrillary tangles in the brain, the produce the neurotrophins in situ. This would theoretically best physical marker of disease progress is in fact loss of syn- help to improve synaptogenicity in the damaged areas and apses between neurons, which most closely correlates with therefore hopefully improve the cognitive decline experienced cognitive decline (Terry et al., 1991; Perez-Cruz et al., 2011; by the patient (Chen and Blurton-Jones, 2012). Neuman et al., 2014). So a possible treatment avenue could be to increase brain synaptogenicity to try and reverse this decline. However, transplanting stem cells does pose some prob- In the healthy brain, synapse formation is modulated by neu- lems. Implanting cells that grow and divide can have the rotrophins (Arancio and Chao, 2007). This idea is also sup- effect of producing a tumour if the growth becomes unregu- ported by the so-called neurotrophic factor hypothesis of AD, lated. One study compared implantation of pluripotent which states that insufficient levels of neurotrophic factors in embryonic stem cells and embryonic stem cell-derived NSCs crucial regions such as the hippocampus result in degeneration into the cortex of an AD mouse model. While the NSCs of neurons, and also indirectly leaves them vulnerable to reduced memory deficits, the pluripotent embryonic stem damage (Yuen et al., 1996; Schinder and Poo, 2000). cells caused worsening of the cognitive defects via teratoma formation (Wang et al., 2006). However, this does demon- Examples of two neurotrophins are nerve growth factor strate the relative safety of using NSCs, since they are only (NGF) and brain-derived neurotrophic factor (BDNF). NGF multipotent and thus less prone to tumour formation in situ. was the first nervous system growth factor to be discovered. A disadvantage of NSCs is that they cannot easily be obtained It is involved in the function and survival of the basal fore- from the human brain, and so studies often use foetal NSCs, brain cholinergic neurons, an area affected by Alzheimer’s which pose ethical problems (Liras, 2010). disease. NGF stimulates a tyrosine kinase receptor expressed by these neurons (TrkA) promoting the maintenance of syn- Another option that has been explored is to genetically aptic contact with hippocampal and cortical neurons modify a fibroblast cell to produce neurotrophins and then (Schleibs, 2011). BDNF is expressed in the entorhinal cortex implant these modified cells into the brain as a source of neu - and is anterogradely transported to the hippocampus where rotrophins. This technique has several advantages. Fibroblasts it is also involved in synapse plasticity and memory (Murer, can easily be obtained from an adult by skin biopsy. This Yan and Raisman-Vozari, 2001). means that there are no associated ethical issues, and that the cells are already matched to the patient. Nevertheless, the In Alzheimer’s, it has been shown that these key neurotroph- cells do have to be genetically modified to express the correct ins are only present at reduced levels (Schulte-Herbruggen, neurotrophin, adding another stage to an already complex Jockers-Scherubl and Hellweg, 2008; Kamei et al., 2007). This procedure. deficiency of neurotrophins leaves their normal role of modu - lating synapse formation unfulfilled, probably leading to Additionally, transplantation of astrocytes has also been reduced synaptic plasticity and resulting in the symptoms of considered as a potential avenue for treatment of Parkinson’s cognitive decline (Kamei et al., 2007). disease (PD). Astrocytes expressing glial-derived neuro- trophic factor (GDNF) were delivered to the striatum of rat and mouse models of PD. Motor improvement was shown in Neurotrophins and stem cells the animals receiving the astrocytes, and importantly, the Stem cells are cells that have the ability to self-renew and dif- GDNF was not transported to other parts of the brain, as it ferentiate into many different cell types. They can be divided had been with other delivery mechanisms, which could cause into two broad groups—pluripotent stem cells, which have the potential side effects (Drinkut et al., 2012). While this shows ability to differentiate into any cell type, and multipotent stem proof of concept of astrocyte transplantation as a delivery cells, which can differentiate into a limited range of cell types, vehicle for GDNF, the authors caution that the results do not depending on their germal origin (Martinez-Morales et al., show clinical efficacy, as the treatment occurred before brain 2 Bioscience Horizons • Volume 7 2014 Review lesions in the animals. Further studies will be needed to eval- is an interesting discovery as all previously tested therapies uate whether this claim can be made. have improved cognition by improving plaque or tangle pathologies in some way, and this approach does neither. This research therefore opens a new avenue of an alternative Neural stem cell transplantation and approach to therapy. BDNF in the 3xTg-AD mouse model The concept of the mechanism of action of the neural stem cells via BDNF was also thoroughly tested. A microfluidic Blurton-Jones et al. (2009) investigated neural stem cell cell culture device (which facilitates axonal analysis) was transplantation as a method to reduce cognitive decline in used to examine axon growth in vitro. Neurons were exposed Alzheimer’s via the action of BDNF. They used a transgenic to three different media—a control conditioned media, NSC- mouse model known as 3xTg-AD to model the effects of conditioned media or NSC-conditioned media where immu- Alzheimer’s disease on the brain. These mice have many of the noprecipitation had been used to remove BDNF. Axonal important pathological features of the disease including outgrowth quantification showed that the NSC-conditioned amyloid-beta plaques and neurofibrillary tangles, and experi - media highly increased axon growth and density compared ence cognitive decline. Although there is no mouse model that with both controls. This suggests that the growth effects pro- exactly mimics all of the features of the human disease and so vided by NSCs are mediated via BDNF. a mouse will not be directly generalizable to human Alzheimer’s sufferers, this model includes many important parallels and so To test the same principle in vivo, lentiviral delivery of conclusions can be drawn bearing this in mind. shRNA was used to stably produce knockdown NSCs, which produce a markedly reduced level of BDNF. Mice were The neural stem cells were grown in vitro and transplanted injected with these stem cells, normal NSCs or an equivalent into the mice via stereotactic injection to the brain. Four volume of vehicle. The knockdown injected mice performed groups of mice were compared—transgenic and wild-type significantly worse on the cognitive tasks than those injected mice were injected with the NSCs, and controls of age- with normal NSCs and no differently from the vehicle- matched transgenic and wild-type mice were injected with a injected controls. Hippocampal synaptic density was also sig- similar volume of vehicle alone. This was an important con- nificantly higher in the normal NSC injected mice than either trol as it has been suggested that brain injection itself could of the other groups (Blurton-Jones et al., 2009). stimulate production of neurotrophins (Cafferty, McGee and Strittmatter, 2008), which would be a confounding variable. This thorough testing of mechanism effectively substanti- The mice were tested on tasks designed to assess cognition ates the paper’s claim that the effects seen in improved cogni- including the Morris Water Maze, and context-dependent tion are in fact mediated via BDNF produced by the NSCs, novel object recognition. They found that the vehicle-injected rather than via another pathway. transgenic mice experienced significantly impaired cognition This study had the advantage that the NSCs grown were compared with their wild-type controls, showing the cogni- tested thoroughly pre-implantation for well-established mark- tive decline caused by the brain pathology they had been ers of multipotency sox-2 and nestin, and coexpression of GFP engineered to develop. The NSC transplant transgenic mice (green fluorescent protein), the fluorescent marker used. This had significant improvements in cognition compared with the shows that the cell lines grown were in fact as the researchers vehicle-injected transgenic mice, showing the benefits that the intended and that they could be identified accurately via fluo - NSC transplant had brought. rescent microscopy. Also the therapy was tested on mice that had extensive brain pathology of plaques and tangles. In The fate of the NSCs was studied in detail 5 weeks after humans, these build up for many years before manifestation of the transplant procedure. Post-mortem tissues were studied symptoms, so it is important to have a therapy that has been microscopically, enabled by fluorescent markers attached to tested in and works despite, extensive pathology. the cells. It was found that the stem cells differentiated into all types of neural cell (astrocytes, oligodendrocytes and neurons) but that the large majority differentiated into astro- Neural stem cell transplantation cytes. The stem cells did not alter the pathology of either in other mouse models plaques or tangles, thought by many to be the causative fea- tures of the disease, but appeared to work by affecting synap- Work has also been done in other mouse models that try tic density in the hippocampus. Post-mortem analysis showed to recapitulate some of the salient features of Alzheimer’s. an increase of 67% in hippocampal synaptic density in the Hampton et al. (2010) used a mouse model of human tauop- NSC transplanted transgenic mice compared with their vehi- athy P301S (). This mouse has an age-related build-up of cle-injected controls. Synaptic density was quantified by mea - hyperphosphorylated human tau in the brain. This causes suring levels of synaptophysin, a presynaptic protein, in the loss of neurons similar to that found in Alzheimer’s. stratum radiatum of the CA1 region of the hippocampus. This is a well-established method, previously used in major They found that after transplanting NSCs into the studies of Alzheimer’s in both mice and humans (Terry et al., transgenic mice, there was a significant increase in number 1991; Mucke et al., 2000). This increase in synaptic density of cortical neurons compared with the non-transplanted 3 Review Bioscience Horizons • Volume 7 2014 contralateral hemisphere of the mouse. The NSCs were clinical tests to assess cognitive function), and PET scans able to counteract the toxic effects on the cells of the mis- assessed activity in affected brain regions. folded tau proteins, allowing cell survival. This is known No adverse effects related to the NGF were reported. Two as a neuroprotective effect. On analysis of the brains of the subjects suffered haemorrhage due to movement during the mice, it was found that the majority of the NSCs had dif- procedure, which was conducted while they were awake and ferentiated into astrocytes. There was also an increase in sedated. Other procedures were performed under general neurotrophins, particularly GDNF (Hampton et al., 2010). anaesthesia and were completed safely. As the NSCs had increased neuron number overall, but not differentiated into neurons themselves, a cell replacement Results showed that cognitive decline appeared to be mechanism of action seems unlikely. Rather, a neuropro- reduced by 36–51% as measured by typical clinical tests over tective effect from the astrocytes produced by the NSCs a mean period of 2 years, compared with preoperative cogni- appeared to be in play, mediated by the effect of secreted tive decline rates. This shows the neuroprotective action of neurotrophins. This is known as a bystander effect. NGF in damaged areas of the brain. PET scans showed However, there was no further study of whether GDNF uptake of glucose was increased in areas of cell delivery. This itself was causing the increase in cortical neurons, so cause usually decreases in Alzheimer’s (Potkin et al., 2001) as dam- and effect cannot be assumed. aged areas are less metabolically active as they are not func- tioning correctly. On post-mortem analysis of a trial member who died 5 weeks post-surgery following a pulmonary Nerve growth factor and embolism, it was found that axon sprouting occurred at site clinical trials of cell delivery. This concurred with results reported from animal models. This shows that the action of the NGF pro- NGF has also been extensively studied as a neurotrophin duced by the cells was to encourage neuronal growth that could help to regenerate the damaged brain. Specifically, (Tuszynski et al., 2005). it has an effect on survival of basal forebrain cholinergic neurons. As this is an area affected in Alzheimer’s, it has However, this study does have limitations that need to be tremendous therapeutic potential for this disease (Tuszynski, taken into account when drawing conclusions from such 2007). data. As a small, non-placebo controlled, non-blinded study involving analysis of seven subjects, bias is likely to be present Initial research was done in animal models. Chen et al. in many areas. modified rat fibroblasts obtained by skin biopsy to secrete NGF using a murine retroviral vector containing human The participants were current patients at the clinic with no beta-NGF cDNA. The NGF secreting fibroblasts were then random selection to avoid bias in the sample, and so are implanted into the brains of ageing rats. They found that unlikely to be representative of the general population. The there was an increase in the number of neurons, and that sample was also very small. This limits generalizability of the memory impairment was reduced, compared with rats receiv- study. Ideally, the study should be placebo controlled with ing a graft of non-engineered fibroblasts. This showed that some patients receiving an injection of an equivalent volume the secreted NGF was acting as a protectant for the neurons, of vehicle to act as the control group. This would give an increasing survival (Chen et al., 2005). important comparison. However, the choice of patients suf- Studies have also been done in primates that are more fering from early stages of the disease was an important one. closely related to humans, and so results are more likely to be These patients are the ones likely to be receiving and benefit - generalizable to the human population. Tuszynski et al. ing most from the therapy if it is proved effective and so are lesioned the fornix of the brains of rhesus monkeys and then the most important group to test it in. transplanted NGF secreting fibroblasts. In the control group, Experimental conditions were different between patients, where fibroblasts that were not modified to secrete NGF were with some receiving bilateral injections of cells and some transplanted, only 25% of cholinergic neurons survived, injections to the right brain only. This limits the conclusions compared with a neuron survival level of 92% in the test that can be drawn from comparison of the subjects. When group. This reiterated the neuroprotective effect of NGF. comparing PET scans, only some subjects received a preop- Because of the level of promising research in this area, it erative scan to act as a control. In the subjects without preop- was felt that a clinical trial was warranted to test the therapy erative scans, more limited conclusions can be drawn in humans. Tuszynski et al. (2005) conducted a Phase 1 clinical without the control comparison. Additionally, no data were trial to test stem cell delivery of NGF as a possible therapy for collected for preoperative rate of decline on the ADAS-Cog Alzheimer’s. Subjects with early-stage, probable Alzheimer’s test. Instead, published averages were used for comparison. were recruited. Skin biopsies were taken from the subjects, and This is not ideal, as there will be inter-patient variation, and fibroblasts were modified to secrete NGF via retroviral vectors. published averages are unlikely to be applicable specifically These were stereotaxically injected into the cholinergic basal to the individual patient. Therefore, more weight should be forebrain in one procedure. Cognitive outcomes were mea- given to the MMSE results, which were collected both pre- sured using MMSE and ADAS-Cog tests (commonly used and post-surgery, and therefore have a valid control. 4 Bioscience Horizons • Volume 7 2014 Review However, the authors took the limitations of their study These cell lines can be used to provide reasonably accurate into account, drawing only tentative conclusions and rec- in vitro models of Alzheimer’s disease, which are crucial for ommending the need for more depth of research into the further research into disease mechanism and can also be used therapy. to test potential new drugs. Overall, further and larger clinical trials are clearly needed, A small-scale study by Goldstein’s research group took but this therapy potentially presents an impressive advance fibroblasts from two patients with familial Alzheimer’s dis - over current treatments that improve cognition by around ease, two patients with sporadic Alzheimer’s disease and two 5% (Mayeux and Sano, 1999) and do not act for an extended subjects without dementia. The fibroblasts were transformed time period. In contrast, the possibility of an improvement of into induced pluripotent stem cells (iPSCs) and these were up to 51% sustained over at least 2 years is very encouraging. grown to cultures of neurons. The results showed that both of the familial Alzheimer’s disease cases and one of the sporadic cases had increased levels of amyloid-beta, phos- Recent developments with MSCs phorylated tau and glycogen synthase kinase 3-beta (GSK3- beta— the enzyme involved in hyperphosphorylation of tau) More recently, human mesenchymal stem cells (MSCs) have compared with the control cases (Israel et al., 2012). This been shown to release protective factors, including BDNF shows that iPSCs can be used to successfully create an in vitro (Chen and Chopp, 2006), into damaged tissues including the model that successfully provides the main hallmarks of the brain (Chamberlain et al., 2007; Ylostalo et al., 2012). This disease. We still do not fully know the cellular processes that makes them an ideal candidate for transplantation. They also contribute to the deterioration of the brain in Alzheimer’s have the benefits of being able to be obtained peripherally, disease, and models such as these provide a fantastic research from blood, adipose tissue or bone marrow (Martinez- opportunity to study these processes in detail. Gonzalez et al., 2006). This means that they are easy to obtain and can be taken from the patient themselves. Moreover, they have none of the ethical issues associated with embryonic Conclusion stem cells. Overall, stem cell transplantation looks to be a field for Animal studies have shown promising results. Lee et al. future development. The ability of stem cells to secrete neu- used a double transgenic mouse model of amyloid precursor roprotective factors allows them to stimulate survival of protein and presenilin-1, and transplanted human umbilical neurons and increase synapse formation, allowing improve- cord derived stem cells into the hippocampus. They found ment of cognitive decline in the otherwise devastating condi- that compared with controls injected with buffer solution, tion of Alzheimer’s. MSCs may also be able to provide a the transplant mice had significantly improved spatial learn - neuroprotective effects, and the results from human trials ing and memory decline, as tested by the Morris water maze, are awaited. Additionally, iPSCs provide a much needed in escape latency, and crossing platform test (Lee et al., 2012). vitro model of human disease, which can be used to study Interestingly, they attributed this to reversal of disease associ- disease processes more closely, and also play a useful role in ated microglial inflammation. They found reduced levels of the testing of potential new drugs. It is clear that more pro-inflammatory cytokines, increased levels of anti- research is needed to bring these experimental therapies into inflammatory cytokines and higher numbers of alternatively practical evidence-based treatments, but the future seems activated microglia, thought to be neuroprotective (Lee et al., bright in this field. 2012). This provides an alternate mechanism of action to the release of neurotrophins. Author’s biography This has led to two human trials of intracerebral infusion of MSCs in patients with Alzheimer’s which are currently R.M. has a First Class BSc (Hons) in Neuroscience and ongoing (NEUROSTEM-AD). It will be very interesting to Mental Health. She is currently studying medicine at Imperial see the outcome of these trials. College London. Her interests include neurology and paedi- atrics. She is looking to become a clinician with a background in research. 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H., Thal, L., Pay, M. et  al. (2005) A phase 1 clinical trial of Zhu, C. W. and Sano, M. (2006) Economic considerations in the manage- nerve growth factor gene therapy for Alzheimer disease, Nature ment of Alzheimer’s disease, Clinical Interventions in Aging, 1 (2), Medicine, 11 (5), 551–555. 143–154. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

Stem cells slow cognitive decline in Alzheimer's disease via neurotrophin action

Bioscience Horizons , Volume 7 – Dec 30, 2014

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BioscienceHorizons Volume 7 2014 10.1093/biohorizons/hzu013 Review Stem cells slow cognitive decline in Alzheimer’s disease via neurotrophin action Rose Mulvey* Imperial College London, Charing Cross Campus, Fulham Palace Road, London W6 8RF, England *Corresponding author: 39 Epirus Road, London SW6 7UR, England. Email: rose.mulvey09@imperial.ac.uk Supervisor: Dr Jane Saffell 411 Burlington Danes, Hammersmith Campus, Du Cane Road, London W12 0NN, England. Email: j.saffell@impeiral.ac.uk Alzheimer’s disease is a growing concern with no satisfactory current treatment solution. Contemporary stem cell research offers a new arena for development in this field. Transplantation of stem cells into the damaged brain brings hope of repair to damaged neurons. This appears to operate via a ‘bystander effect’ whereby neurotrophins secreted by the cells act as a neuro - protectant, rather than a cell replacement mechanism as some have postulated. Such treatments can slow or even reverse cognitive decline. Research into neural stem cell transplantation has shown reversal of cognitive decline in animal models of disease via the mechanism of brain-derived neurotrophic factor secretion. Studies using nerve growth factor secreting stem cells have showed promising results with cognitive decline reversed in animal models of the disease. A Phase 1 clinical trial also showed promising reversal of cognitive decline in human subjects using transplantation of nerve growth factor secreting fibroblasts. Mesenchymal stem cells have also shown promise, and results from human trials are awaited. Induced pluripotent stem cells have provided a successful model of human disease in vitro. Although early results from transplant studies are encouraging, a lot more research will be needed before these preliminary advances can be translated to therapies with a strong evidence base to be used in practice. Key words: Alzheimer’s, stem cells, transplantation, BDNF, NGF, cognitive decline Submitted on 3 April 2014; accepted on 4 December 2014 Alzheimer’s disease is the most common form of dementia. patients who need long-term care solutions. Additionally, and There is no cure, and current treatments are palliative and arguably more importantly, Alzheimer’s puts a huge emo- offer a symptomatic relief of a limited duration. Pathologically, tional burden on caregivers and family members, who are the brain suffers from loss of neurons and decreased numbers forced to watch loved ones slowly lose their abilities and per- of synapses, with a build-up of plaques of amyloid-beta pro- sonalities. With an estimated one in two people over the age tein and fibrillary tangles of tau protein, leading to disruption of 85 set to suffer from the disease (Zhu and Sano, 2006), this of normal function and eventually cell death. This occurs in predicament may be all too close to home for many of us. specific areas of the brain including the hippocampus, basal Currently, NICE recommend only four treatments for forebrain cholinergic neurons and areas of the cortex that are Alzheimer’s. Three of the four: donezipil, rivastigmine and involved in learning and memory. The disease manifests in galantamine are acetylcholinesterase inhibitors. These prolong problems of memory and learning, and general cognitive the presence of acetylcholine (a neurotransmitter involved in decline that worsens over time. memory function) at the synapse, by blocking the enzyme With the number of sufferers set to rise to 42.2 million acetylcholinesterase. This slows deterioration of cognitive worldwide by 2020 and 81.1 million by 2040 (Ferri et al., function in patients with mild to moderate disease (Wolfson 2005), this clearly poses a great problem for healthcare pro- et al., 2002; Birks, 2006; Prvulovic and Schneider, 2014). The viders, not least one of funding to support large numbers of fourth, memantine is an NMDA receptor antagonist. It p revents © 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/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  Review Bioscience Horizons • Volume 7 2014 excitatory glutamate neurotoxicity (Choi, 1992) and has been 2013). For example, neural stem cells (NSCs) can differentiate shown to be effective in severe dementia (Di Santo et al., into neurons, astrocytes or oligodendrocytes (Taupin, 2006). 2013). With these treatments only able to slow cognitive In adults, NSCs are found in the subgranular zone and decline for a period, before allowing the disease to resume its subventricular zone of the hippocampus (Taupin, 2006), part course, there is real need for disease modifying therapies that of the brain which is important for learning and memory could halt cognitive decline or even reverse its course. A poten- (Deng, Aimone and Gage, 2010). tial new drug, Dimebon, an antihistamine, recently showed promise in early trials (Doody et al., 2008), but then it failed in NSCs express high levels of neurotrophins including BDNF Phase III clinical trials (Miller, 2010). It would seem that a new and NGF (Lu et al., 2003; Kamei et al., 2007). Transplantation approach to the problem is needed. of these cells into areas of pathology in the brain would there- fore present a mechanism of delivery of these factors directly to the brain which avoids the difficulty of the factors being Neurotrophin activity unable to cross the blood–brain barrier, a problem intrinsic to Research has shown that despite the obvious pathological hall- more peripheral methods of delivery. A stem cell graft would marks of protein plaques and fibrillary tangles in the brain, the produce the neurotrophins in situ. This would theoretically best physical marker of disease progress is in fact loss of syn- help to improve synaptogenicity in the damaged areas and apses between neurons, which most closely correlates with therefore hopefully improve the cognitive decline experienced cognitive decline (Terry et al., 1991; Perez-Cruz et al., 2011; by the patient (Chen and Blurton-Jones, 2012). Neuman et al., 2014). So a possible treatment avenue could be to increase brain synaptogenicity to try and reverse this decline. However, transplanting stem cells does pose some prob- In the healthy brain, synapse formation is modulated by neu- lems. Implanting cells that grow and divide can have the rotrophins (Arancio and Chao, 2007). This idea is also sup- effect of producing a tumour if the growth becomes unregu- ported by the so-called neurotrophic factor hypothesis of AD, lated. One study compared implantation of pluripotent which states that insufficient levels of neurotrophic factors in embryonic stem cells and embryonic stem cell-derived NSCs crucial regions such as the hippocampus result in degeneration into the cortex of an AD mouse model. While the NSCs of neurons, and also indirectly leaves them vulnerable to reduced memory deficits, the pluripotent embryonic stem damage (Yuen et al., 1996; Schinder and Poo, 2000). cells caused worsening of the cognitive defects via teratoma formation (Wang et al., 2006). However, this does demon- Examples of two neurotrophins are nerve growth factor strate the relative safety of using NSCs, since they are only (NGF) and brain-derived neurotrophic factor (BDNF). NGF multipotent and thus less prone to tumour formation in situ. was the first nervous system growth factor to be discovered. A disadvantage of NSCs is that they cannot easily be obtained It is involved in the function and survival of the basal fore- from the human brain, and so studies often use foetal NSCs, brain cholinergic neurons, an area affected by Alzheimer’s which pose ethical problems (Liras, 2010). disease. NGF stimulates a tyrosine kinase receptor expressed by these neurons (TrkA) promoting the maintenance of syn- Another option that has been explored is to genetically aptic contact with hippocampal and cortical neurons modify a fibroblast cell to produce neurotrophins and then (Schleibs, 2011). BDNF is expressed in the entorhinal cortex implant these modified cells into the brain as a source of neu - and is anterogradely transported to the hippocampus where rotrophins. This technique has several advantages. Fibroblasts it is also involved in synapse plasticity and memory (Murer, can easily be obtained from an adult by skin biopsy. This Yan and Raisman-Vozari, 2001). means that there are no associated ethical issues, and that the cells are already matched to the patient. Nevertheless, the In Alzheimer’s, it has been shown that these key neurotroph- cells do have to be genetically modified to express the correct ins are only present at reduced levels (Schulte-Herbruggen, neurotrophin, adding another stage to an already complex Jockers-Scherubl and Hellweg, 2008; Kamei et al., 2007). This procedure. deficiency of neurotrophins leaves their normal role of modu - lating synapse formation unfulfilled, probably leading to Additionally, transplantation of astrocytes has also been reduced synaptic plasticity and resulting in the symptoms of considered as a potential avenue for treatment of Parkinson’s cognitive decline (Kamei et al., 2007). disease (PD). Astrocytes expressing glial-derived neuro- trophic factor (GDNF) were delivered to the striatum of rat and mouse models of PD. Motor improvement was shown in Neurotrophins and stem cells the animals receiving the astrocytes, and importantly, the Stem cells are cells that have the ability to self-renew and dif- GDNF was not transported to other parts of the brain, as it ferentiate into many different cell types. They can be divided had been with other delivery mechanisms, which could cause into two broad groups—pluripotent stem cells, which have the potential side effects (Drinkut et al., 2012). While this shows ability to differentiate into any cell type, and multipotent stem proof of concept of astrocyte transplantation as a delivery cells, which can differentiate into a limited range of cell types, vehicle for GDNF, the authors caution that the results do not depending on their germal origin (Martinez-Morales et al., show clinical efficacy, as the treatment occurred before brain 2 Bioscience Horizons • Volume 7 2014 Review lesions in the animals. Further studies will be needed to eval- is an interesting discovery as all previously tested therapies uate whether this claim can be made. have improved cognition by improving plaque or tangle pathologies in some way, and this approach does neither. This research therefore opens a new avenue of an alternative Neural stem cell transplantation and approach to therapy. BDNF in the 3xTg-AD mouse model The concept of the mechanism of action of the neural stem cells via BDNF was also thoroughly tested. A microfluidic Blurton-Jones et al. (2009) investigated neural stem cell cell culture device (which facilitates axonal analysis) was transplantation as a method to reduce cognitive decline in used to examine axon growth in vitro. Neurons were exposed Alzheimer’s via the action of BDNF. They used a transgenic to three different media—a control conditioned media, NSC- mouse model known as 3xTg-AD to model the effects of conditioned media or NSC-conditioned media where immu- Alzheimer’s disease on the brain. These mice have many of the noprecipitation had been used to remove BDNF. Axonal important pathological features of the disease including outgrowth quantification showed that the NSC-conditioned amyloid-beta plaques and neurofibrillary tangles, and experi - media highly increased axon growth and density compared ence cognitive decline. Although there is no mouse model that with both controls. This suggests that the growth effects pro- exactly mimics all of the features of the human disease and so vided by NSCs are mediated via BDNF. a mouse will not be directly generalizable to human Alzheimer’s sufferers, this model includes many important parallels and so To test the same principle in vivo, lentiviral delivery of conclusions can be drawn bearing this in mind. shRNA was used to stably produce knockdown NSCs, which produce a markedly reduced level of BDNF. Mice were The neural stem cells were grown in vitro and transplanted injected with these stem cells, normal NSCs or an equivalent into the mice via stereotactic injection to the brain. Four volume of vehicle. The knockdown injected mice performed groups of mice were compared—transgenic and wild-type significantly worse on the cognitive tasks than those injected mice were injected with the NSCs, and controls of age- with normal NSCs and no differently from the vehicle- matched transgenic and wild-type mice were injected with a injected controls. Hippocampal synaptic density was also sig- similar volume of vehicle alone. This was an important con- nificantly higher in the normal NSC injected mice than either trol as it has been suggested that brain injection itself could of the other groups (Blurton-Jones et al., 2009). stimulate production of neurotrophins (Cafferty, McGee and Strittmatter, 2008), which would be a confounding variable. This thorough testing of mechanism effectively substanti- The mice were tested on tasks designed to assess cognition ates the paper’s claim that the effects seen in improved cogni- including the Morris Water Maze, and context-dependent tion are in fact mediated via BDNF produced by the NSCs, novel object recognition. They found that the vehicle-injected rather than via another pathway. transgenic mice experienced significantly impaired cognition This study had the advantage that the NSCs grown were compared with their wild-type controls, showing the cogni- tested thoroughly pre-implantation for well-established mark- tive decline caused by the brain pathology they had been ers of multipotency sox-2 and nestin, and coexpression of GFP engineered to develop. The NSC transplant transgenic mice (green fluorescent protein), the fluorescent marker used. This had significant improvements in cognition compared with the shows that the cell lines grown were in fact as the researchers vehicle-injected transgenic mice, showing the benefits that the intended and that they could be identified accurately via fluo - NSC transplant had brought. rescent microscopy. Also the therapy was tested on mice that had extensive brain pathology of plaques and tangles. In The fate of the NSCs was studied in detail 5 weeks after humans, these build up for many years before manifestation of the transplant procedure. Post-mortem tissues were studied symptoms, so it is important to have a therapy that has been microscopically, enabled by fluorescent markers attached to tested in and works despite, extensive pathology. the cells. It was found that the stem cells differentiated into all types of neural cell (astrocytes, oligodendrocytes and neurons) but that the large majority differentiated into astro- Neural stem cell transplantation cytes. The stem cells did not alter the pathology of either in other mouse models plaques or tangles, thought by many to be the causative fea- tures of the disease, but appeared to work by affecting synap- Work has also been done in other mouse models that try tic density in the hippocampus. Post-mortem analysis showed to recapitulate some of the salient features of Alzheimer’s. an increase of 67% in hippocampal synaptic density in the Hampton et al. (2010) used a mouse model of human tauop- NSC transplanted transgenic mice compared with their vehi- athy P301S (). This mouse has an age-related build-up of cle-injected controls. Synaptic density was quantified by mea - hyperphosphorylated human tau in the brain. This causes suring levels of synaptophysin, a presynaptic protein, in the loss of neurons similar to that found in Alzheimer’s. stratum radiatum of the CA1 region of the hippocampus. This is a well-established method, previously used in major They found that after transplanting NSCs into the studies of Alzheimer’s in both mice and humans (Terry et al., transgenic mice, there was a significant increase in number 1991; Mucke et al., 2000). This increase in synaptic density of cortical neurons compared with the non-transplanted 3 Review Bioscience Horizons • Volume 7 2014 contralateral hemisphere of the mouse. The NSCs were clinical tests to assess cognitive function), and PET scans able to counteract the toxic effects on the cells of the mis- assessed activity in affected brain regions. folded tau proteins, allowing cell survival. This is known No adverse effects related to the NGF were reported. Two as a neuroprotective effect. On analysis of the brains of the subjects suffered haemorrhage due to movement during the mice, it was found that the majority of the NSCs had dif- procedure, which was conducted while they were awake and ferentiated into astrocytes. There was also an increase in sedated. Other procedures were performed under general neurotrophins, particularly GDNF (Hampton et al., 2010). anaesthesia and were completed safely. As the NSCs had increased neuron number overall, but not differentiated into neurons themselves, a cell replacement Results showed that cognitive decline appeared to be mechanism of action seems unlikely. Rather, a neuropro- reduced by 36–51% as measured by typical clinical tests over tective effect from the astrocytes produced by the NSCs a mean period of 2 years, compared with preoperative cogni- appeared to be in play, mediated by the effect of secreted tive decline rates. This shows the neuroprotective action of neurotrophins. This is known as a bystander effect. NGF in damaged areas of the brain. PET scans showed However, there was no further study of whether GDNF uptake of glucose was increased in areas of cell delivery. This itself was causing the increase in cortical neurons, so cause usually decreases in Alzheimer’s (Potkin et al., 2001) as dam- and effect cannot be assumed. aged areas are less metabolically active as they are not func- tioning correctly. On post-mortem analysis of a trial member who died 5 weeks post-surgery following a pulmonary Nerve growth factor and embolism, it was found that axon sprouting occurred at site clinical trials of cell delivery. This concurred with results reported from animal models. This shows that the action of the NGF pro- NGF has also been extensively studied as a neurotrophin duced by the cells was to encourage neuronal growth that could help to regenerate the damaged brain. Specifically, (Tuszynski et al., 2005). it has an effect on survival of basal forebrain cholinergic neurons. As this is an area affected in Alzheimer’s, it has However, this study does have limitations that need to be tremendous therapeutic potential for this disease (Tuszynski, taken into account when drawing conclusions from such 2007). data. As a small, non-placebo controlled, non-blinded study involving analysis of seven subjects, bias is likely to be present Initial research was done in animal models. Chen et al. in many areas. modified rat fibroblasts obtained by skin biopsy to secrete NGF using a murine retroviral vector containing human The participants were current patients at the clinic with no beta-NGF cDNA. The NGF secreting fibroblasts were then random selection to avoid bias in the sample, and so are implanted into the brains of ageing rats. They found that unlikely to be representative of the general population. The there was an increase in the number of neurons, and that sample was also very small. This limits generalizability of the memory impairment was reduced, compared with rats receiv- study. Ideally, the study should be placebo controlled with ing a graft of non-engineered fibroblasts. This showed that some patients receiving an injection of an equivalent volume the secreted NGF was acting as a protectant for the neurons, of vehicle to act as the control group. This would give an increasing survival (Chen et al., 2005). important comparison. However, the choice of patients suf- Studies have also been done in primates that are more fering from early stages of the disease was an important one. closely related to humans, and so results are more likely to be These patients are the ones likely to be receiving and benefit - generalizable to the human population. Tuszynski et al. ing most from the therapy if it is proved effective and so are lesioned the fornix of the brains of rhesus monkeys and then the most important group to test it in. transplanted NGF secreting fibroblasts. In the control group, Experimental conditions were different between patients, where fibroblasts that were not modified to secrete NGF were with some receiving bilateral injections of cells and some transplanted, only 25% of cholinergic neurons survived, injections to the right brain only. This limits the conclusions compared with a neuron survival level of 92% in the test that can be drawn from comparison of the subjects. When group. This reiterated the neuroprotective effect of NGF. comparing PET scans, only some subjects received a preop- Because of the level of promising research in this area, it erative scan to act as a control. In the subjects without preop- was felt that a clinical trial was warranted to test the therapy erative scans, more limited conclusions can be drawn in humans. Tuszynski et al. (2005) conducted a Phase 1 clinical without the control comparison. Additionally, no data were trial to test stem cell delivery of NGF as a possible therapy for collected for preoperative rate of decline on the ADAS-Cog Alzheimer’s. Subjects with early-stage, probable Alzheimer’s test. Instead, published averages were used for comparison. were recruited. Skin biopsies were taken from the subjects, and This is not ideal, as there will be inter-patient variation, and fibroblasts were modified to secrete NGF via retroviral vectors. published averages are unlikely to be applicable specifically These were stereotaxically injected into the cholinergic basal to the individual patient. Therefore, more weight should be forebrain in one procedure. Cognitive outcomes were mea- given to the MMSE results, which were collected both pre- sured using MMSE and ADAS-Cog tests (commonly used and post-surgery, and therefore have a valid control. 4 Bioscience Horizons • Volume 7 2014 Review However, the authors took the limitations of their study These cell lines can be used to provide reasonably accurate into account, drawing only tentative conclusions and rec- in vitro models of Alzheimer’s disease, which are crucial for ommending the need for more depth of research into the further research into disease mechanism and can also be used therapy. to test potential new drugs. Overall, further and larger clinical trials are clearly needed, A small-scale study by Goldstein’s research group took but this therapy potentially presents an impressive advance fibroblasts from two patients with familial Alzheimer’s dis - over current treatments that improve cognition by around ease, two patients with sporadic Alzheimer’s disease and two 5% (Mayeux and Sano, 1999) and do not act for an extended subjects without dementia. The fibroblasts were transformed time period. In contrast, the possibility of an improvement of into induced pluripotent stem cells (iPSCs) and these were up to 51% sustained over at least 2 years is very encouraging. grown to cultures of neurons. The results showed that both of the familial Alzheimer’s disease cases and one of the sporadic cases had increased levels of amyloid-beta, phos- Recent developments with MSCs phorylated tau and glycogen synthase kinase 3-beta (GSK3- beta— the enzyme involved in hyperphosphorylation of tau) More recently, human mesenchymal stem cells (MSCs) have compared with the control cases (Israel et al., 2012). This been shown to release protective factors, including BDNF shows that iPSCs can be used to successfully create an in vitro (Chen and Chopp, 2006), into damaged tissues including the model that successfully provides the main hallmarks of the brain (Chamberlain et al., 2007; Ylostalo et al., 2012). This disease. We still do not fully know the cellular processes that makes them an ideal candidate for transplantation. They also contribute to the deterioration of the brain in Alzheimer’s have the benefits of being able to be obtained peripherally, disease, and models such as these provide a fantastic research from blood, adipose tissue or bone marrow (Martinez- opportunity to study these processes in detail. Gonzalez et al., 2006). This means that they are easy to obtain and can be taken from the patient themselves. Moreover, they have none of the ethical issues associated with embryonic Conclusion stem cells. Overall, stem cell transplantation looks to be a field for Animal studies have shown promising results. Lee et al. future development. The ability of stem cells to secrete neu- used a double transgenic mouse model of amyloid precursor roprotective factors allows them to stimulate survival of protein and presenilin-1, and transplanted human umbilical neurons and increase synapse formation, allowing improve- cord derived stem cells into the hippocampus. They found ment of cognitive decline in the otherwise devastating condi- that compared with controls injected with buffer solution, tion of Alzheimer’s. MSCs may also be able to provide a the transplant mice had significantly improved spatial learn - neuroprotective effects, and the results from human trials ing and memory decline, as tested by the Morris water maze, are awaited. Additionally, iPSCs provide a much needed in escape latency, and crossing platform test (Lee et al., 2012). vitro model of human disease, which can be used to study Interestingly, they attributed this to reversal of disease associ- disease processes more closely, and also play a useful role in ated microglial inflammation. They found reduced levels of the testing of potential new drugs. It is clear that more pro-inflammatory cytokines, increased levels of anti- research is needed to bring these experimental therapies into inflammatory cytokines and higher numbers of alternatively practical evidence-based treatments, but the future seems activated microglia, thought to be neuroprotective (Lee et al., bright in this field. 2012). This provides an alternate mechanism of action to the release of neurotrophins. Author’s biography This has led to two human trials of intracerebral infusion of MSCs in patients with Alzheimer’s which are currently R.M. has a First Class BSc (Hons) in Neuroscience and ongoing (NEUROSTEM-AD). It will be very interesting to Mental Health. She is currently studying medicine at Imperial see the outcome of these trials. College London. Her interests include neurology and paedi- atrics. She is looking to become a clinician with a background in research. 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Bioscience HorizonsOxford University Press

Published: Dec 30, 2014

Keywords: Alzheimer's stem cells transplantation BDNF NGF cognitive decline

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