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Stem cell therapy for Alzheimer's disease: hype or hope?

Stem cell therapy for Alzheimer's disease: hype or hope? BioscienceHorizons Volume 6 2013 10.1093/biohorizons/hzt011 Review article Stem cell therapy for Alzheimer’s disease: hype or hope? Alan King Lun Liu* Imperial College London, South Kensington Campus, London SW7 2AZ, UK *Corresponding author: Neuropathology Unit, Department of Medicine, Imperial College London, 11/F, Laboratory Block, Charing Cross Hospital, St Dunstan’s Road, London W6 8RP, UK. Email: king.liu09@imperial.ac.uk Project supervisor: Dr Jane Saffell, Deputy Head Development, Division of Brain Sciences, Department of Medicine, Burlington Danes, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting millions of people in the world. Cognitive impairments such as progressive memory loss are devastating manifestations from this disease. Current pharmacological treatment has limited efficacy and only provides symptomatic relief without long-term cure. As a result, cell-replacement therapy using stem cells is an emerging potential treatment to AD. In the last decade, there have been animal trials using stem cells to treat and modulate cognitive impairment in AD models via three different mechanisms—replacing the damaged or dead cholinergic neurons; protecting neurons by reducing toxic amyloid protein aggregates or insoluble tau neurofibrillary tangles and promoting neurogenesis in hippocampus by neurotrophic secretions from stem cells. All of the trials showed promising results and improved our understandings about the mechanism of dementia in AD. With the continued improve- ment in safety profile of stem cell therapy and the creation of a better animal AD model in which to test them, it is feasible that stem cells could be trialled in humans for AD treatment in the next 5–10 years. Keywords: Alzheimer’s disease, stem cells, neurogenesis, cognition, memory, animal models Submitted 21 December 2012; accepted on 14 October 2013 Introduction classical hallmarks of AD. Aβ plaques are misfolded protein accumulated extracellularly, which are neurotoxic, and could Currently, Alzheimer’s disease (AD) is the commonest cause lead to neuronal loss. Neurofibrillary tangles are insoluble of dementia (Dantuma, Merchant and Sugaya, 2010) affect- aggregates of hyperphosphorylated tau protein, an intracel- ing over 24 million people worldwide (Ferri et al., 2005). For lular cytoskeletal molecule (Mattson, 2004; Blennow, de adults over 60s, dementia is even the fourth greatest global Leon and Zetterberg, 2006). Although the causative mecha- disease burden according to a World Health Organisation nism between Aβ plaques and tau neurofibrillary tangles is (2003) report published in 2003. Because of the gradual age- still unclear, it is thought the combination of both leads to ing population, it has been predicted that around 81 million neuronal and synaptic loss in various cortical regions in the people will have dementia by 2040 (Ferri et al., 2005). brain, resulting in cognitive decline and memory loss Patients with AD suffer from memory dysfunction and inabil- (Dantuma, Merchant and Sugaya, 2010). ity to learn, and some can develop psychotic symptoms such Cholinergic neurons in the brain are especially vulnerable to as hallucination and delusions (Blennow, de Leon and damage by AD (Geula et al., 2008). They produce the neu- Zetterberg, 2006). The disease was first described by a rotransmitter acetylcholine, which is important in the control German neuropathologist, Alos Alzheimer (Goedert and of sleep–wake cycle, consciousness, learning and memory pro- Spillantini, 2006). He identified the presence of amyloid-beta cessing (Schliebs and Arendt, 2011). These neurons originate (Aβ) plaques and neurofibrillary tangles in the brain as two © The Author 2013. 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Review article Bioscience Horizons • Volume 6 2013 from the basal forebrain, in a region known as the nucleus that the NSCs survived and were differentiated into neurons basalis of Meynert (nbM) and project to various cortical and astrocytes in the rats’ brains. Also, a significant improve- regions in the brain (Selden et al., 1998). In AD, a hypothesis ment in cognitive function for the aged rats with memory called the ‘cholinergic hypothesis’ states that the level of cog- impairment was observed after the transplantation compared nitive decline in the AD patient directly correlates with the with the control, correlating with the differentiated neurons decrease of cholinergic neurons in the nbM (Bartus et al., in the hippocampus. However, the neuronal marker used in 1982). To rescue the effects of the damaged cholinergic neu- this study, βIII tubulin, only labels immature neurons. rons, there are two types of drugs currently used in AD Therefore, further physiological investigations were required patients—acetylcholinesterase inhibitors such as donepezil to prove that neurons derived from the NSCs were fully func- and galantamine, which prevent the degradation of acetyl- tional. The group also discovered an increase in the astrocyte choline at the synapse, and memantine, an N-methyl-d- density within a part of the hippocampus (outside of the aspartate receptor antagonist, which protects cholinergic transplantation site) where astrocytes are not normally neuronal death from excitotoxicity (Roberson and Mucke, found. Because astrocytes are important structural and meta- 2006). However, these drugs have variable efficacy and only bolic support cells within the brain (Doetsch, 2003), this sug- provide symptomatic reliefs without long-term cure gests NSCs do not only replace or strengthen the neural (Borlongan, 2012). Therefore, a novel treatment is needed to circuit but they might also create an environment for the be found to cure AD. Recently, there have been advance- growth and support for neuronal fibres (Isacson et al., 1995). ments using stem cell therapy to successfully treat neurologi- Pluripotent ES cells were once thought to be an ideal can- cal conditions such as stroke, Parkinson’s disease, spinal cord didate for stem cell therapy as they have the most potential to injury and amyotrophic lateral sclerosis (Lu et al., 2003; divide and differentiate. However, safety is the greatest con- Goldman, 2005; Park et al., 2006; Ebert et al., 2008; Kim cern for the use of ES cells. One group compared the use of and de Vellis, 2009). As a result, the therapeutic potential of ES cells and ES cell-derived NSCs by transplanting them into stem cell in restoring cognition has been investigated exten- the cortex of a mouse model of AD (Wang et al., 2006). They sively. Over the past few years, there has been growing evi- found the cognitive deficits actually worsened with ES cell dence from different animal trials (Table 1). Here I will transplantation because the stem cells induced a teratoma review recent studies that have used stem cell therapy in ani- (a tumour with mixed cell types). Moreover, the use of mal models of AD or cognitive decline and consider the effec- embryonic cells generates much ethical debate (Juengst and tiveness of this approach for restoring cognitive function. Fossel, 2000), hence NSCs are more commonly used. Unfortunately, NSCs are very difficult to obtain from Which stem cell to use? adult’s brain and so current studies mainly use foetal NSCs, which could also generate ethical problems. Very recently, it Stem cells are characterized by their unique properties of self- was found that MSCs derived from bone marrow, umbilical renewal and their ability to differentiate into different cell cord blood and adipose tissue could be transdifferentiated lineages (Dantuma, Merchant and Sugaya, 2010). There are into neuronal cells (Brazelton et al., 2000; Mezey et al., 2000; many types of stem cells in the body which can broadly be Kim et al., 2012). Studies using MSC transplantation on AD divided into embryonic and adult (somatic) stem cells. animal models have shown promising results on their Embryonic stem (ES) cells are pluripotent, which means they improvement in cognitive function (Babaei, Soltani Tehrani have the ability to differentiate into different germ layers giv- and Alizadeh, 2012; Lee et al., 2012). Babaei, Soltani Tehrani ing rise to different types of progenitor cells. ES cells develop and Alizadeh (2012) induced an nbM lesion in the rats with into multipotent adult stem cells such as neural stem cells an excitotoxin to model cognitive decline in AD. The rats (NSCs) and mesenchymal stem cells (MSCs), which can only then received either MSC or a sham infusion into the hippo- differentiate into a specific cell type (Mimeault, Hauke and campus. They showed that learning and memory significantly Batra, 2007). improved in the group which received MSCs compared with NSCs reside within the brain and can be differentiated the sham infusion. As the MSCs were derived from rat tibia, into neurons, astrocytes and oligodendrocytes (Taupin, this shows we might be able to harvest stem cells from the 2006). Originally, it was thought that neurogenesis only adult bone marrow to develop a treatment for AD. However, takes place in the foetus. However, recent studies showed no neuropathological investigation was done in this study to that this process also happens in adult’s brain and NSCs were correlate the outcome with the differentiation of MSCs into found in the subgranular zone (SGZ) and subventricular zone functional neurons in the hippocampus. Also, interspecies (SVZ) (Taupin, 2006; Mu and Gage, 2011). The SGZ is variation could mean the results shown were only applicable located within the hippocampus, part of the brain which is when using murine MSCs. Therefore, it would be useful to important in learning and memory formation (Squire, 1992). transplant MSCs from human bone marrow and include neu- Therefore, it seems like NSCs are obvious choice for the ropathological investigations to look at survival and differen- replacement of damaged neurons. Qu et al. (2001) were one tiation of MSCs in future studies. In another study, MSCs of the earliest groups to prove this by implanting human derived from human umbilical cord blood were transplanted NSCs into the brains of aged and mature rats. They showed into the hippocampus of transgenic mice model of AD 2 Bioscience Horizons • Volume 6 2013 Review article Table 1. Summary of recent stem cell therapy studies on animal models of AD and cognitive decline Types of stem Models/methods of Outcome in cognition and/or pathology in the Study cell Transplant site cognitive decline induction brain post-transplantation transplanted 1. Aged rats—learn more rapidly 1. Aged rats (30 months) Babaei et al. Murine Hippocampus 2. Ibo-induced memory impairment group—sig- 2. Ibotenic acid-induced (2012) BM-MSC (CA-1 region) nificant reduction in latency to find platform in NBM lesion rats Morris Water Maze NSC transplant rescues learning and memory Blurton- Triple transgenic AD model deficits Jones et al. mNSC Hippocampus mice (3xTg-AD) No change in Aβ, tau pathology but increased (2009) synaptic density in mice’s hippocampus Significant improvement in cognitive tasks (Y-maze Esmaeilzade Rat hippocampal Aβ EPI-NCSC Hippocampus and passive avoidance tests), increased neuron et al. (2012) injection number and differentiation into other cell type Kern et al. Decreased tau-positive clusters in trisomic (28.6%) mNSC DS model mice (Ts65Dn) Hippocampus (2011) and disomic (58.6%) mice Both intravenous and intracerebral ASC transplan- 1. Intravenous tation rescued memory impairment and improved Kim et al. Transgenic AD-model mice 2. Hippocampus spatial learning; Human ASC (2012) (Tg2576) (bilateral Reduced amyloid plaque formation, upregulated dentate gyrus) interleukin-10 and neurotrophic factors in the brain of Tg2576 mice Lee et al. Murine Acute Aβ-induced model Hippocampus BM-MSCs promoted microglial activation (2009) BM-MSC mice (dentate gyrus) Reduced Aβ deposits of acutely induced AD mice Improved spatial learning and memory in Morris Water Maze tests Lee et al. Human APP and presenilin (PS1) Hippocampus Reduced Aβ load and tau hyperphosphorylation, (2012) UCB-MSC double-transgenic mice inhibited proinflammatory cytokine release from microglia Park et al. Intracerebro- hNSC Aged rats (22 months) SGZ increased in cell number (2010) ventricular Rats receiving NSCs overexpressing ChAT showed Park et al. AF64A cholinotoxin injection Right lateral full recovery in learning and memory functions, hNSC (2012) in rats ventricle whereas those receiving NSCs only remained memory impaired 1. Matured rats (6 months) Cognitive function significantly improved in Qu et al. 2. Aged rats (24 months)— Right lateral matured and aged memory-impaired groups hNSC (2001) memory impaired and ventricle Morphologically functional hNSC-derived cells unimpaired were found in the hippocampus and cortex Murine ES and Frontal association NPC restored memory, ES significantly decrease Wang et al. Ibotenic acid-induced NBM ES-derived cortex and barrel working memory; ES induced massive teratoma (2006) lesion mice NSC field of S1 cortex formation mNSC and Improved memory and learning in Y-maze testing; Xuan et al. Rat Fimbria-Fornix NSC-derived Basal forebrain Increased in the number of p75NGFR-positive (2009) transaction glial cells neurons Double transgenic neuronal Yamasaki Improved hippocampal-dependent memory and mNSC injury model mice (CaM/ Hippocampus et al. (2007) increased synaptic density and neuronal number Tet-DT ) Aβ, amyloid-beta; AD, Alzheimer’s disease; APP, amyloid precursor protein; ASC, adipose-derived stem cell; BM-MSC, bone marrow mesenchy- mal stem cell; ChAT, choline-acetyltransferase; EPI-NCSC, epidermal neural crest stem cell; ES, embryonic stem cell; NGFR, nerve growth factor receptor; NSC, human neural stem cell; hNSC, human neural stem cell; mNSC, murine neural stem cell; UCB-MSC, umbilical cord blood mesenchymal stem cell. 3 Review article Bioscience Horizons • Volume 6 2013 (Lee et al., 2012). In this case, not only did the transplanted This means the transplanted NSCs might actually be affected group show significant improvement in cognitive function, by the cholinotoxin. Hence, only the genetically programmed Aβ deposition in the brain and hyperphosphorylated tau NSCs could overcome the effect by over-synthesizing were also decreased. The change in the AD pathology was ChAT enzyme. Nevertheless, this study suggests the simple associated with the modulation in neuroinflammation in replacement of cholinergic neurons is not sufficient in restor - which an upregulation of anti-inflammatory cytokines was ing cognitive function in AD. found. These results were promising that it prompted for fur- ther research on humans to correlate neuroinflammation Clearing up the misfolded protein with AD, and the use of MSCs could potentially be developed aggregates using stem cell therapy as a novel immunomodulatory treatment for AD. As previously mentioned, Aβ plaques and tau neurofibrillary tangles are toxic aggregates, which might damage neurons in Replacing cholinergic neurons with the brain. Since implanted stem cells typically differentiate stem cells and migrate to areas with neuronal loss (Imitola et al., 2004), Cholinergic neurons that originate from the nbM are essen- would stem cells have a role in the clearance of the misfolded tial for cognitive functioning. Therefore, an induced lesion protein? To tackle this question, Kern et al. (2011) investi- on the cholinergic system is commonly used as AD models to gated the effects of neural stem cell transplantation in the determine whether stem cell therapy could replace choliner- mice model of Down syndrome (DS). DS and AD are similar gic neurons and restore cognitive function. Xuan et al. in a way that many patients with DS have progressive mem- (2009) demonstrated that engrafted NSCs do increase the ory decline and possess typical plaques and tangles on neuro- number of cholinergic neurons and enhance memory and pathological studies. In this particular mouse model, there is learning in AD-model rats. They simulated cognitive impair- neuronal cell loss and an increase in tau-clustered granules ment by performing a unilateral fimbria–fornix transaction especially in the hippocampal region. The group implanted in the rat’s brain to disrupt the cholinergic neuronal circuit murine NSCs or saline as a control into the hippocampus of between the brain septum and the hippocampus. Significant DS mice. One month after transplantation, they found the improvement in learning and memory was observed after number of tau clusters were significantly lower in the NSC- transplantation of the NSCs. Also, immunohistochemistry transplanted group, suggesting NSCs might have a role in the studies showed that a significantly higher number of cholin- reduction of tau aggregates. Interestingly, the clearance of tau ergic neurons were found on the transplanted group com- neurofibrillary tangles was also found on the opposite side of pared with the lesioned group. However, the study did not the transplantation without the migration of NSCs. This sug- show whether the stem cells actually differentiate into gests NSCs do not physically reduce tau tangles, but soluble cholinergic neurons or whether the NSCs were secreting growth factors secreted by NSCs might regulate tau phos- neurotrophic factors to stimulate neurogenesis. Interestingly, phorylation throughout the brain. However, it would be NSCs seem to preferably differentiate into glial cells, which wrong to assume that the same will happen in humans as the are structural neuronal cells. But there were no improvement appearance of tau neurofibrillary tangles is different between in cognitive function nor an increase in cholinergic neurons humans and mouse (Gotz, 2001), which is one main flaw of when isolated glial cells were transplanted into the rats’ this study. brains. This suggests glial cells do not have a direct role in Another group has looked at bone marrow-derived MSC’s cognitive functioning, but their presence might be important role in the reduction of brain Aβ plaques. Lee, Jin and Bae for NSCs to stimulate neurogenesis to replace or protect (2009) injected soluble aggregated Aβ into the mouse hippo- cholinergic neurons. campus to induce an acute AD model. They transplanted Since the replacement of cholinergic neurons is important murine MSCs from the bone marrow into the hippocampus to restore memory and learning, would it not be more effi- and found Aβ deposition disappeared after 7 days of trans- cient if we transplant cells that could secrete more acetylcho- plantation. Activated microglia, the macrophages in the line? Park et al. (2012) answered this question by brain, was shown to be increased in the transplanted group transplanting NSCs, which are genetically programmed to compared with the control. The study therefore concluded over-express choline acetyltransferase (ChAT), an enzyme that grafted bone marrow–MSCs might induce microglial used for the synthesis of acetylcholine, into an AD-model rat. activation and recruitment, leading to phagocytosis to clear They found that the modified NSCs synthesized more ChAT up Aβ plaques in the brain (Lee, Jin and Bae, 2009). than the normal NSCs and could significantly improve cogni- tive function. However, strangely, they showed normal NSCs Altering neurogenesis to restore had actually no effects on restoring memory on the rats. One memory function major caveat about this study is the model they used to simu- late cognitive decline in AD. A cholinotoxin, AF64A, was From the two studies above, stem cells were shown to reduce used to reduce the release of acetylcholine in the brain by or protect neurons from toxic aggregation of misfolded pro- altering ChAT mRNA expression in cholinergic neurons. tein. However, both studies failed to investigate the effects of 4 Bioscience Horizons • Volume 6 2013 Review article plaques or neurofibrillary tangles clearance on cognitive familial (Young and Goldstein, 2012) and there are yet no function. A year later, Blurton-Jones et al. (2009) published a animal models which can simulate the sporadic and progres- study showing that cognitive decline in a transgenic mice sive nature of AD. Moreover, co-morbidity factors such as model of AD could actually be rescued by NSC therapy age and cardiovascular events could not be accounted for in without altering the levels of Aβ or tau protein. Interestingly, current AD models (Borlongan, 2012). a previous imaging study showed similar findings which sug- Recent animal studies have shown that learning and mem- gested that plaques and tangles could accumulate for many ory deficit could be improved by stem cell therapy. But, in all years before cognitive function starts declining (Kemppainen studies, the assessments of cognitive improvement were per- et al., 2007). Blurton-Jones et al. (2009) also demonstrated formed only shortly after stem cell transplantation without that cognitive improvement correlated positively with neuro- much follow-up. As AD is a progressive disease, longer term genesis as they found an increase in brain-derived neuro- studies are needed to look at lasting effects as well as safety trophic factor (BDNF), which has role in synaptogenesis and profile of the treatments (Borlongan, 2012). neuronal networking (Aguado et al., 2003). From this we could hypothesize that the cause of dementia in AD is due to With the recent advancements of reprogramming technol- the reduction in neurogenesis caused by the exhaustion of ogy, there is a great potential in the use of inducible pluripo- NSCs from long-term toxic damage by Aβ plaques or tau tent stem cell (iPSC) in the treatment of AD. Somatic cells neurofibrillary tangles. Post-mortem immunohistochemical from patients could be reprogrammed to generate iPSCs, studies in AD cases to investigate co-localization between which could then be directed into the differentiation of neural NSCs and aggregated proteins could be helpful to identify the precursor cells for transplantation (Jung et al., 2012). This interaction between Aβ, tau and NSCs. means tissue rejections due to immunological incompatibility will no longer be an issue and there will be fewer ethical prob- Increasing evidence has shown that cognitive function is lems. Also, it can improve the modelling of neurodegenerative linked to the alteration of neurogenesis in the adult hippo- diseases like AD because iPSCs could differentiate into neu- campus. Surprisingly, it emerges that depression could also be rons, which contain the unique genetic phenotype of the caused by a decrease in hippocampal neurogenesis (Duman, patient (Young and Goldstein, 2012). This creates a model 2004) like AD and antidepressive medication could promote which offers the closest approximation to the sporadic form neurogenesis in the hippocampus of rodents. Therefore, of the disease and hopefully could be translated into human Chang et al. (2012) carried out an in vitro study which dem- studies to find a cure for AD. onstrated that fluoxetine, an antidepressant, could stimulate NSCs proliferation and protect stem cells from Aβ cytotoxic- ity (Chang et al., 2012). This provides a potential use of Conclusion fluoxetine in future studies of stem cell transplantation in Stem cell therapy in recent years has shown promising results restoring cognitive function. in rescuing cognitive decline on animal models of AD. These With regard to stem cell therapy, it is now believed that help us understand more about cognitive functioning and the the increase in neurogenesis rather than purely the replace- mechanisms which leads to memory loss in AD. More evi- ment of cholinergic neurons leads to an improvement in cog- dence has also shown that the decline of neurogenesis, rather nition. As mentioned earlier, stem cells could provide a than simply the accumulation of protein aggregates, contrib- neurotrophic environment by the production of BDNF utes to dementia in the AD patients. Therefore, future studies (Blurton-Jones et al., 2009). They could also differentiate should focus on using stem cells to deliver neurotrophic fac- into glial cells which secrete different neurotrophic factors tors for the alteration of neurogenesis in AD models. (Xuan et al., 2009) to promote neurogenesis. Therefore, in However, most of the current research is hype as there were future studies, we might see the rise in the use of genetically safety (e.g. ES induced tumourigenesis) and ethical issues modified stem cells to deliver neurotrophic factors, which involved in the use of foetal stem cells. Also, there is not a stimulate neurogenesis for the treatment of cognitive decline single animal model which could simulate the full aspect of in AD models. AD. Nevertheless, there is still hope—the use of MSCs is free from ethical problems and could potentially be a type of immunomodulatory treatment for AD. Also, with the The future of stem cell therapy for advancement in the use of iPSC, hopefully we could model Alzheimer’s disease the disease better and eventually translate stem cell research into human studies with the aim to finally solve the enigma of AD is a complex disease which affects different neural cell restoring the memory. types and has a diffuse pathology (Chen and Blurton-Jones, 2012). Therefore, there are limitations on the animal studies as only certain aspects of AD could be modelled. Transgenic Acknowledgement models of AD are the most current animal model used, which display the nature of cognitive decline with typical AD The author would like to thank Dr Jane Saffell for her guid- pathology in familial AD. However, only <5% of AD is ance and constructive feedback. 5 Review article Bioscience Horizons • Volume 6 2013 Ferri, C. P., Prince, M., Brayne, C. et  al. and Alzheimer’s Disease Author biography International. (2005) Global prevalence of dementia: a Delphi con- sensus study, Lancet, 366 (9503), 2112–2117. A.K.L.L. is a fourth year medical student currently studying an intercalated BSc in Neuroscience and Mental Health at Geula, C., Nagykery, N., Nicholas, A. et  al. (2008) Cholinergic neuronal Imperial College London. He has a particular interest in and axonal abnormalities are present early in aging and in Alzheimer prion disease, neurodegenerative conditions and cognitive disease, Journal of Neuropathology and Experimental Neurology, 67 neuroscience. 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Stem cell therapy for Alzheimer's disease: hype or hope?

Liu, Alan King Lun
Bioscience Horizons , Volume 6 – Dec 5, 2013
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BioscienceHorizons Volume 6 2013 10.1093/biohorizons/hzt011 Review article Stem cell therapy for Alzheimer’s disease: hype or hope? Alan King Lun Liu* Imperial College London, South Kensington Campus, London SW7 2AZ, UK *Corresponding author: Neuropathology Unit, Department of Medicine, Imperial College London, 11/F, Laboratory Block, Charing Cross Hospital, St Dunstan’s Road, London W6 8RP, UK. Email: king.liu09@imperial.ac.uk Project supervisor: Dr Jane Saffell, Deputy Head Development, Division of Brain Sciences, Department of Medicine, Burlington Danes, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting millions of people in the world. Cognitive impairments such as progressive memory loss are devastating manifestations from this disease. Current pharmacological treatment has limited efficacy and only provides symptomatic relief without long-term cure. As a result, cell-replacement therapy using stem cells is an emerging potential treatment to AD. In the last decade, there have been animal trials using stem cells to treat and modulate cognitive impairment in AD models via three different mechanisms—replacing the damaged or dead cholinergic neurons; protecting neurons by reducing toxic amyloid protein aggregates or insoluble tau neurofibrillary tangles and promoting neurogenesis in hippocampus by neurotrophic secretions from stem cells. All of the trials showed promising results and improved our understandings about the mechanism of dementia in AD. With the continued improve- ment in safety profile of stem cell therapy and the creation of a better animal AD model in which to test them, it is feasible that stem cells could be trialled in humans for AD treatment in the next 5–10 years. Keywords: Alzheimer’s disease, stem cells, neurogenesis, cognition, memory, animal models Submitted 21 December 2012; accepted on 14 October 2013 Introduction classical hallmarks of AD. Aβ plaques are misfolded protein accumulated extracellularly, which are neurotoxic, and could Currently, Alzheimer’s disease (AD) is the commonest cause lead to neuronal loss. Neurofibrillary tangles are insoluble of dementia (Dantuma, Merchant and Sugaya, 2010) affect- aggregates of hyperphosphorylated tau protein, an intracel- ing over 24 million people worldwide (Ferri et al., 2005). For lular cytoskeletal molecule (Mattson, 2004; Blennow, de adults over 60s, dementia is even the fourth greatest global Leon and Zetterberg, 2006). Although the causative mecha- disease burden according to a World Health Organisation nism between Aβ plaques and tau neurofibrillary tangles is (2003) report published in 2003. Because of the gradual age- still unclear, it is thought the combination of both leads to ing population, it has been predicted that around 81 million neuronal and synaptic loss in various cortical regions in the people will have dementia by 2040 (Ferri et al., 2005). brain, resulting in cognitive decline and memory loss Patients with AD suffer from memory dysfunction and inabil- (Dantuma, Merchant and Sugaya, 2010). ity to learn, and some can develop psychotic symptoms such Cholinergic neurons in the brain are especially vulnerable to as hallucination and delusions (Blennow, de Leon and damage by AD (Geula et al., 2008). They produce the neu- Zetterberg, 2006). The disease was first described by a rotransmitter acetylcholine, which is important in the control German neuropathologist, Alos Alzheimer (Goedert and of sleep–wake cycle, consciousness, learning and memory pro- Spillantini, 2006). He identified the presence of amyloid-beta cessing (Schliebs and Arendt, 2011). These neurons originate (Aβ) plaques and neurofibrillary tangles in the brain as two © The Author 2013. 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Review article Bioscience Horizons • Volume 6 2013 from the basal forebrain, in a region known as the nucleus that the NSCs survived and were differentiated into neurons basalis of Meynert (nbM) and project to various cortical and astrocytes in the rats’ brains. Also, a significant improve- regions in the brain (Selden et al., 1998). In AD, a hypothesis ment in cognitive function for the aged rats with memory called the ‘cholinergic hypothesis’ states that the level of cog- impairment was observed after the transplantation compared nitive decline in the AD patient directly correlates with the with the control, correlating with the differentiated neurons decrease of cholinergic neurons in the nbM (Bartus et al., in the hippocampus. However, the neuronal marker used in 1982). To rescue the effects of the damaged cholinergic neu- this study, βIII tubulin, only labels immature neurons. rons, there are two types of drugs currently used in AD Therefore, further physiological investigations were required patients—acetylcholinesterase inhibitors such as donepezil to prove that neurons derived from the NSCs were fully func- and galantamine, which prevent the degradation of acetyl- tional. The group also discovered an increase in the astrocyte choline at the synapse, and memantine, an N-methyl-d- density within a part of the hippocampus (outside of the aspartate receptor antagonist, which protects cholinergic transplantation site) where astrocytes are not normally neuronal death from excitotoxicity (Roberson and Mucke, found. Because astrocytes are important structural and meta- 2006). However, these drugs have variable efficacy and only bolic support cells within the brain (Doetsch, 2003), this sug- provide symptomatic reliefs without long-term cure gests NSCs do not only replace or strengthen the neural (Borlongan, 2012). Therefore, a novel treatment is needed to circuit but they might also create an environment for the be found to cure AD. Recently, there have been advance- growth and support for neuronal fibres (Isacson et al., 1995). ments using stem cell therapy to successfully treat neurologi- Pluripotent ES cells were once thought to be an ideal can- cal conditions such as stroke, Parkinson’s disease, spinal cord didate for stem cell therapy as they have the most potential to injury and amyotrophic lateral sclerosis (Lu et al., 2003; divide and differentiate. However, safety is the greatest con- Goldman, 2005; Park et al., 2006; Ebert et al., 2008; Kim cern for the use of ES cells. One group compared the use of and de Vellis, 2009). As a result, the therapeutic potential of ES cells and ES cell-derived NSCs by transplanting them into stem cell in restoring cognition has been investigated exten- the cortex of a mouse model of AD (Wang et al., 2006). They sively. Over the past few years, there has been growing evi- found the cognitive deficits actually worsened with ES cell dence from different animal trials (Table 1). Here I will transplantation because the stem cells induced a teratoma review recent studies that have used stem cell therapy in ani- (a tumour with mixed cell types). Moreover, the use of mal models of AD or cognitive decline and consider the effec- embryonic cells generates much ethical debate (Juengst and tiveness of this approach for restoring cognitive function. Fossel, 2000), hence NSCs are more commonly used. Unfortunately, NSCs are very difficult to obtain from Which stem cell to use? adult’s brain and so current studies mainly use foetal NSCs, which could also generate ethical problems. Very recently, it Stem cells are characterized by their unique properties of self- was found that MSCs derived from bone marrow, umbilical renewal and their ability to differentiate into different cell cord blood and adipose tissue could be transdifferentiated lineages (Dantuma, Merchant and Sugaya, 2010). There are into neuronal cells (Brazelton et al., 2000; Mezey et al., 2000; many types of stem cells in the body which can broadly be Kim et al., 2012). Studies using MSC transplantation on AD divided into embryonic and adult (somatic) stem cells. animal models have shown promising results on their Embryonic stem (ES) cells are pluripotent, which means they improvement in cognitive function (Babaei, Soltani Tehrani have the ability to differentiate into different germ layers giv- and Alizadeh, 2012; Lee et al., 2012). Babaei, Soltani Tehrani ing rise to different types of progenitor cells. ES cells develop and Alizadeh (2012) induced an nbM lesion in the rats with into multipotent adult stem cells such as neural stem cells an excitotoxin to model cognitive decline in AD. The rats (NSCs) and mesenchymal stem cells (MSCs), which can only then received either MSC or a sham infusion into the hippo- differentiate into a specific cell type (Mimeault, Hauke and campus. They showed that learning and memory significantly Batra, 2007). improved in the group which received MSCs compared with NSCs reside within the brain and can be differentiated the sham infusion. As the MSCs were derived from rat tibia, into neurons, astrocytes and oligodendrocytes (Taupin, this shows we might be able to harvest stem cells from the 2006). Originally, it was thought that neurogenesis only adult bone marrow to develop a treatment for AD. However, takes place in the foetus. However, recent studies showed no neuropathological investigation was done in this study to that this process also happens in adult’s brain and NSCs were correlate the outcome with the differentiation of MSCs into found in the subgranular zone (SGZ) and subventricular zone functional neurons in the hippocampus. Also, interspecies (SVZ) (Taupin, 2006; Mu and Gage, 2011). The SGZ is variation could mean the results shown were only applicable located within the hippocampus, part of the brain which is when using murine MSCs. Therefore, it would be useful to important in learning and memory formation (Squire, 1992). transplant MSCs from human bone marrow and include neu- Therefore, it seems like NSCs are obvious choice for the ropathological investigations to look at survival and differen- replacement of damaged neurons. Qu et al. (2001) were one tiation of MSCs in future studies. In another study, MSCs of the earliest groups to prove this by implanting human derived from human umbilical cord blood were transplanted NSCs into the brains of aged and mature rats. They showed into the hippocampus of transgenic mice model of AD 2 Bioscience Horizons • Volume 6 2013 Review article Table 1. Summary of recent stem cell therapy studies on animal models of AD and cognitive decline Types of stem Models/methods of Outcome in cognition and/or pathology in the Study cell Transplant site cognitive decline induction brain post-transplantation transplanted 1. Aged rats—learn more rapidly 1. Aged rats (30 months) Babaei et al. Murine Hippocampus 2. Ibo-induced memory impairment group—sig- 2. Ibotenic acid-induced (2012) BM-MSC (CA-1 region) nificant reduction in latency to find platform in NBM lesion rats Morris Water Maze NSC transplant rescues learning and memory Blurton- Triple transgenic AD model deficits Jones et al. mNSC Hippocampus mice (3xTg-AD) No change in Aβ, tau pathology but increased (2009) synaptic density in mice’s hippocampus Significant improvement in cognitive tasks (Y-maze Esmaeilzade Rat hippocampal Aβ EPI-NCSC Hippocampus and passive avoidance tests), increased neuron et al. (2012) injection number and differentiation into other cell type Kern et al. Decreased tau-positive clusters in trisomic (28.6%) mNSC DS model mice (Ts65Dn) Hippocampus (2011) and disomic (58.6%) mice Both intravenous and intracerebral ASC transplan- 1. Intravenous tation rescued memory impairment and improved Kim et al. Transgenic AD-model mice 2. Hippocampus spatial learning; Human ASC (2012) (Tg2576) (bilateral Reduced amyloid plaque formation, upregulated dentate gyrus) interleukin-10 and neurotrophic factors in the brain of Tg2576 mice Lee et al. Murine Acute Aβ-induced model Hippocampus BM-MSCs promoted microglial activation (2009) BM-MSC mice (dentate gyrus) Reduced Aβ deposits of acutely induced AD mice Improved spatial learning and memory in Morris Water Maze tests Lee et al. Human APP and presenilin (PS1) Hippocampus Reduced Aβ load and tau hyperphosphorylation, (2012) UCB-MSC double-transgenic mice inhibited proinflammatory cytokine release from microglia Park et al. Intracerebro- hNSC Aged rats (22 months) SGZ increased in cell number (2010) ventricular Rats receiving NSCs overexpressing ChAT showed Park et al. AF64A cholinotoxin injection Right lateral full recovery in learning and memory functions, hNSC (2012) in rats ventricle whereas those receiving NSCs only remained memory impaired 1. Matured rats (6 months) Cognitive function significantly improved in Qu et al. 2. Aged rats (24 months)— Right lateral matured and aged memory-impaired groups hNSC (2001) memory impaired and ventricle Morphologically functional hNSC-derived cells unimpaired were found in the hippocampus and cortex Murine ES and Frontal association NPC restored memory, ES significantly decrease Wang et al. Ibotenic acid-induced NBM ES-derived cortex and barrel working memory; ES induced massive teratoma (2006) lesion mice NSC field of S1 cortex formation mNSC and Improved memory and learning in Y-maze testing; Xuan et al. Rat Fimbria-Fornix NSC-derived Basal forebrain Increased in the number of p75NGFR-positive (2009) transaction glial cells neurons Double transgenic neuronal Yamasaki Improved hippocampal-dependent memory and mNSC injury model mice (CaM/ Hippocampus et al. (2007) increased synaptic density and neuronal number Tet-DT ) Aβ, amyloid-beta; AD, Alzheimer’s disease; APP, amyloid precursor protein; ASC, adipose-derived stem cell; BM-MSC, bone marrow mesenchy- mal stem cell; ChAT, choline-acetyltransferase; EPI-NCSC, epidermal neural crest stem cell; ES, embryonic stem cell; NGFR, nerve growth factor receptor; NSC, human neural stem cell; hNSC, human neural stem cell; mNSC, murine neural stem cell; UCB-MSC, umbilical cord blood mesenchymal stem cell. 3 Review article Bioscience Horizons • Volume 6 2013 (Lee et al., 2012). In this case, not only did the transplanted This means the transplanted NSCs might actually be affected group show significant improvement in cognitive function, by the cholinotoxin. Hence, only the genetically programmed Aβ deposition in the brain and hyperphosphorylated tau NSCs could overcome the effect by over-synthesizing were also decreased. The change in the AD pathology was ChAT enzyme. Nevertheless, this study suggests the simple associated with the modulation in neuroinflammation in replacement of cholinergic neurons is not sufficient in restor - which an upregulation of anti-inflammatory cytokines was ing cognitive function in AD. found. These results were promising that it prompted for fur- ther research on humans to correlate neuroinflammation Clearing up the misfolded protein with AD, and the use of MSCs could potentially be developed aggregates using stem cell therapy as a novel immunomodulatory treatment for AD. As previously mentioned, Aβ plaques and tau neurofibrillary tangles are toxic aggregates, which might damage neurons in Replacing cholinergic neurons with the brain. Since implanted stem cells typically differentiate stem cells and migrate to areas with neuronal loss (Imitola et al., 2004), Cholinergic neurons that originate from the nbM are essen- would stem cells have a role in the clearance of the misfolded tial for cognitive functioning. Therefore, an induced lesion protein? To tackle this question, Kern et al. (2011) investi- on the cholinergic system is commonly used as AD models to gated the effects of neural stem cell transplantation in the determine whether stem cell therapy could replace choliner- mice model of Down syndrome (DS). DS and AD are similar gic neurons and restore cognitive function. Xuan et al. in a way that many patients with DS have progressive mem- (2009) demonstrated that engrafted NSCs do increase the ory decline and possess typical plaques and tangles on neuro- number of cholinergic neurons and enhance memory and pathological studies. In this particular mouse model, there is learning in AD-model rats. They simulated cognitive impair- neuronal cell loss and an increase in tau-clustered granules ment by performing a unilateral fimbria–fornix transaction especially in the hippocampal region. The group implanted in the rat’s brain to disrupt the cholinergic neuronal circuit murine NSCs or saline as a control into the hippocampus of between the brain septum and the hippocampus. Significant DS mice. One month after transplantation, they found the improvement in learning and memory was observed after number of tau clusters were significantly lower in the NSC- transplantation of the NSCs. Also, immunohistochemistry transplanted group, suggesting NSCs might have a role in the studies showed that a significantly higher number of cholin- reduction of tau aggregates. Interestingly, the clearance of tau ergic neurons were found on the transplanted group com- neurofibrillary tangles was also found on the opposite side of pared with the lesioned group. However, the study did not the transplantation without the migration of NSCs. This sug- show whether the stem cells actually differentiate into gests NSCs do not physically reduce tau tangles, but soluble cholinergic neurons or whether the NSCs were secreting growth factors secreted by NSCs might regulate tau phos- neurotrophic factors to stimulate neurogenesis. Interestingly, phorylation throughout the brain. However, it would be NSCs seem to preferably differentiate into glial cells, which wrong to assume that the same will happen in humans as the are structural neuronal cells. But there were no improvement appearance of tau neurofibrillary tangles is different between in cognitive function nor an increase in cholinergic neurons humans and mouse (Gotz, 2001), which is one main flaw of when isolated glial cells were transplanted into the rats’ this study. brains. This suggests glial cells do not have a direct role in Another group has looked at bone marrow-derived MSC’s cognitive functioning, but their presence might be important role in the reduction of brain Aβ plaques. Lee, Jin and Bae for NSCs to stimulate neurogenesis to replace or protect (2009) injected soluble aggregated Aβ into the mouse hippo- cholinergic neurons. campus to induce an acute AD model. They transplanted Since the replacement of cholinergic neurons is important murine MSCs from the bone marrow into the hippocampus to restore memory and learning, would it not be more effi- and found Aβ deposition disappeared after 7 days of trans- cient if we transplant cells that could secrete more acetylcho- plantation. Activated microglia, the macrophages in the line? Park et al. (2012) answered this question by brain, was shown to be increased in the transplanted group transplanting NSCs, which are genetically programmed to compared with the control. The study therefore concluded over-express choline acetyltransferase (ChAT), an enzyme that grafted bone marrow–MSCs might induce microglial used for the synthesis of acetylcholine, into an AD-model rat. activation and recruitment, leading to phagocytosis to clear They found that the modified NSCs synthesized more ChAT up Aβ plaques in the brain (Lee, Jin and Bae, 2009). than the normal NSCs and could significantly improve cogni- tive function. However, strangely, they showed normal NSCs Altering neurogenesis to restore had actually no effects on restoring memory on the rats. One memory function major caveat about this study is the model they used to simu- late cognitive decline in AD. A cholinotoxin, AF64A, was From the two studies above, stem cells were shown to reduce used to reduce the release of acetylcholine in the brain by or protect neurons from toxic aggregation of misfolded pro- altering ChAT mRNA expression in cholinergic neurons. tein. However, both studies failed to investigate the effects of 4 Bioscience Horizons • Volume 6 2013 Review article plaques or neurofibrillary tangles clearance on cognitive familial (Young and Goldstein, 2012) and there are yet no function. A year later, Blurton-Jones et al. (2009) published a animal models which can simulate the sporadic and progres- study showing that cognitive decline in a transgenic mice sive nature of AD. Moreover, co-morbidity factors such as model of AD could actually be rescued by NSC therapy age and cardiovascular events could not be accounted for in without altering the levels of Aβ or tau protein. Interestingly, current AD models (Borlongan, 2012). a previous imaging study showed similar findings which sug- Recent animal studies have shown that learning and mem- gested that plaques and tangles could accumulate for many ory deficit could be improved by stem cell therapy. But, in all years before cognitive function starts declining (Kemppainen studies, the assessments of cognitive improvement were per- et al., 2007). Blurton-Jones et al. (2009) also demonstrated formed only shortly after stem cell transplantation without that cognitive improvement correlated positively with neuro- much follow-up. As AD is a progressive disease, longer term genesis as they found an increase in brain-derived neuro- studies are needed to look at lasting effects as well as safety trophic factor (BDNF), which has role in synaptogenesis and profile of the treatments (Borlongan, 2012). neuronal networking (Aguado et al., 2003). From this we could hypothesize that the cause of dementia in AD is due to With the recent advancements of reprogramming technol- the reduction in neurogenesis caused by the exhaustion of ogy, there is a great potential in the use of inducible pluripo- NSCs from long-term toxic damage by Aβ plaques or tau tent stem cell (iPSC) in the treatment of AD. Somatic cells neurofibrillary tangles. Post-mortem immunohistochemical from patients could be reprogrammed to generate iPSCs, studies in AD cases to investigate co-localization between which could then be directed into the differentiation of neural NSCs and aggregated proteins could be helpful to identify the precursor cells for transplantation (Jung et al., 2012). This interaction between Aβ, tau and NSCs. means tissue rejections due to immunological incompatibility will no longer be an issue and there will be fewer ethical prob- Increasing evidence has shown that cognitive function is lems. Also, it can improve the modelling of neurodegenerative linked to the alteration of neurogenesis in the adult hippo- diseases like AD because iPSCs could differentiate into neu- campus. Surprisingly, it emerges that depression could also be rons, which contain the unique genetic phenotype of the caused by a decrease in hippocampal neurogenesis (Duman, patient (Young and Goldstein, 2012). This creates a model 2004) like AD and antidepressive medication could promote which offers the closest approximation to the sporadic form neurogenesis in the hippocampus of rodents. Therefore, of the disease and hopefully could be translated into human Chang et al. (2012) carried out an in vitro study which dem- studies to find a cure for AD. onstrated that fluoxetine, an antidepressant, could stimulate NSCs proliferation and protect stem cells from Aβ cytotoxic- ity (Chang et al., 2012). This provides a potential use of Conclusion fluoxetine in future studies of stem cell transplantation in Stem cell therapy in recent years has shown promising results restoring cognitive function. in rescuing cognitive decline on animal models of AD. These With regard to stem cell therapy, it is now believed that help us understand more about cognitive functioning and the the increase in neurogenesis rather than purely the replace- mechanisms which leads to memory loss in AD. More evi- ment of cholinergic neurons leads to an improvement in cog- dence has also shown that the decline of neurogenesis, rather nition. As mentioned earlier, stem cells could provide a than simply the accumulation of protein aggregates, contrib- neurotrophic environment by the production of BDNF utes to dementia in the AD patients. Therefore, future studies (Blurton-Jones et al., 2009). They could also differentiate should focus on using stem cells to deliver neurotrophic fac- into glial cells which secrete different neurotrophic factors tors for the alteration of neurogenesis in AD models. (Xuan et al., 2009) to promote neurogenesis. Therefore, in However, most of the current research is hype as there were future studies, we might see the rise in the use of genetically safety (e.g. ES induced tumourigenesis) and ethical issues modified stem cells to deliver neurotrophic factors, which involved in the use of foetal stem cells. Also, there is not a stimulate neurogenesis for the treatment of cognitive decline single animal model which could simulate the full aspect of in AD models. AD. Nevertheless, there is still hope—the use of MSCs is free from ethical problems and could potentially be a type of immunomodulatory treatment for AD. Also, with the The future of stem cell therapy for advancement in the use of iPSC, hopefully we could model Alzheimer’s disease the disease better and eventually translate stem cell research into human studies with the aim to finally solve the enigma of AD is a complex disease which affects different neural cell restoring the memory. types and has a diffuse pathology (Chen and Blurton-Jones, 2012). Therefore, there are limitations on the animal studies as only certain aspects of AD could be modelled. Transgenic Acknowledgement models of AD are the most current animal model used, which display the nature of cognitive decline with typical AD The author would like to thank Dr Jane Saffell for her guid- pathology in familial AD. However, only <5% of AD is ance and constructive feedback. 5 Review article Bioscience Horizons • Volume 6 2013 Ferri, C. P., Prince, M., Brayne, C. et  al. and Alzheimer’s Disease Author biography International. (2005) Global prevalence of dementia: a Delphi con- sensus study, Lancet, 366 (9503), 2112–2117. A.K.L.L. is a fourth year medical student currently studying an intercalated BSc in Neuroscience and Mental Health at Geula, C., Nagykery, N., Nicholas, A. et  al. (2008) Cholinergic neuronal Imperial College London. He has a particular interest in and axonal abnormalities are present early in aging and in Alzheimer prion disease, neurodegenerative conditions and cognitive disease, Journal of Neuropathology and Experimental Neurology, 67 neuroscience. 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Journal

Bioscience Horizons – Oxford University Press

Published: Dec 5, 2013

Keywords: Alzheimer's disease stem cells neurogenesis cognition memory animal models

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