Liyan Qiao(?), Hongyun Huang, Lin Chen

?

Cell‐based therapy in Alzheimer’s disease: Current knowledge and perspective

Liyan Qiao1(?), Hongyun Huang2,3, Lin Chen4

1Department of Neurology, Tsinghua University Yuquan Hospital, Beijing 100040, China

2Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing 100039, China3Beijing Hongtianji Neuroscience Academy, Lingxiu Building, Beijing 100043, China

4Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing 100040, China

ARTICLE INFO

Received: 8 January 2016

Revised: 29 February 2016

Accepted: 29 February 2016

? The authors 2016. This article is published with open access at www.TNCjournal.com

KEYWORDS

Alzheimer’s disease;

cell therapy;

stem cells;

neurogenesis

ABSTRACT

Alzheimer’s disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by the deposition of insoluble β‐amyloid (Aβ) peptides, intracellular neurofibrillary tangles, amyloid angiopathy, age‐related brain atrophy, synaptic pathology, white matter rarefaction, granulovacuolar degeneration, neuron loss, and neuroinflammation. Although much is known about the neurobiology of AD, very few conventional therapies are available to arrest or slow the disease. There is an urgent need for novel therapeutic approaches for AD. AD subjects have significantly fewer viable precursor cells in the hippocampus compared with age‐matched healthy control subjects. However, the viable precursor cells that remain in AD and age‐matched healthy control brain specimens can be induced to differentiate. To facilitate or mimic the natural compensatory effect in AD, cell therapy, including endogenous and exogenous stem cells, has been considered in AD. In this review, we focus on the history and development of cell therapy in AD, and consider the role of cell therapy as a potential treatment for AD.

Citation Qiao LY, Huang HY, Chen L. Cell‐based therapy in Alzheimer’s disease: Current knowledge and perspective. Transl. Neurosci. Clin. 2016, 2(1): 50–58.

? Corresponding author: Liyan Qiao, E-mail: qiaoliyan2000@aliyun.com

1 Introduction

Alzheimer’s disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by the deposition of insoluble β‐amyloid (Aβ) peptides, intracellular neurofibrillary tangles, amyloid angiopathy, age‐related brain atrophy, synaptic pathology, white matter rarefaction, granulovacuolar degeneration, neuron loss, and neuroinflammation. An estimated 5.3 million Americans have AD, 5.1 million are over the age of 65 years and approximately 200,000 are aged < 65 years and have younger onset AD. By the mid‐21st century, the number of people living with AD in the United States is projected to grow to nearly 10 million[1].

With the exception of the rare cases caused by known genetic mutations, AD, similar to other common chronic diseases, typically develops as a result of multiple factors rather than a single cause. Known risk factors for AD include age, family history, presence of the apolipoprotein (Apo)E ε4 gene, mild cognitive impairment, traumatic brain injury, cardiovascular disease risk factors, lack of social and cognitive engagement, and lower educational level[1].

Abnormal accumulation of Aβ peptide is widely believed to be the underlying mechanism of thepathologic and clinical changes seen in AD[2]. Aβ appears earliest in the cerebral neocortex, prior to the onset of symptoms, and reaches the cerebellar cortex in advanced clinical disease[3]. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles[4]. Cholinergic dysfunction in the basal and rostral forebrain is associated with early cognitive impairments observed in AD[5]. In addition to the abnormal accumulation of Aβ peptide, formation of neurofibrillary tangles, and degeneration of the cholinergic pathway, AD has also been associated with environmental and genetic factors, mitochondrial dysfunction, vascular factors, immune system dysfunction, and infectious agents. Neurovascular dysfunction plays an essential role in this multifactorial pattern. The neurovascular unit encompasses neurons, interneurons, astrocytes, smooth muscle cells, pericytes, endothelial cells, and the extracellular matrix[6]. A broad spectrum of insults to the neurovascular unit, including breakdown of the blood–brain barrier, cerebral amyloid angiopathy, abnormal or loss of cholinergic innervation of blood vessels, arterial hypercontractility, atherosclerosis, vascular anatomical defects, mitochondrial abnormalities of the endothelial cells, and degeneration of pericytes, has been implicated[7, 8].

In patients with AD, a dysfunctional presynaptic cholinergic system is one of the causes for the cognitive disorders involved in patients where decreased activity of choline acetyltransferase (ChAT), which is responsible for acetylcholine (ACh) synthesis, is seen[9]. The common drugs used in the treatment of AD are acetylcholinesterase inhibitors and memantine (the latter blocks the effects of excessive levels of glutamate that may lead to neuronal dysfunction), which have been shown to improve cognitive performances and stabilize the functional ability of patients. However, none of the treatments available for AD have been shown to slow or stop the dysfunction and death of neurons in the brain that cause the symptoms of AD. The discovery of neural stem cells and neurogenesis is the foundation for cell therapy in AD and other diseases. Recently, cell therapy has become the pre‐ferred term replacing stem cell therapy, due to the fact that a mixture of cell types are applied, although stem cells are the main components in these cell mixtures.

In this review, we focus on the history and development of cell therapy in AD, and consider the role of cell therapy as a potential treatment for AD.

2 Cell‐based therapy in AD

2.1 The discovery of adult neural stem cells (NSCs)

and neurogenesis

Altman first observed dividing cells in the subven‐tricular zone (SVZ) and speculated that neurogenesis occurred in the adult rat and cat dentate gyrus (DG)[10, 11]. In 1965, Altman and Das provided the first strong evidence for neurogenesis in the adult brain[12], reporting on the migration of cells born postnatally in the SVZ, which matured into neurons in the olfactory bulb. In 1969, Altman was the first to describe the rostral migratory stream, which is located between the SVZ and olfactory bulb and serves as the migratory path for the NSCs born in the SVZ[13]. Adult neurogenesis also takes place in humans[14].

There are two major specialized neurogenic regions that exist in the adult mammalian brain where endogenous NSCs reside—the SVZ lining the lateral ventricles and the subgranular zone (SGZ) within the DG of the hippocampus.

2.2 Cell kinds for cell therapy in AD

Stem cells are characterized by two fundamental properties: the ability to self‐renew and the ability to give rise to differentiated progeny. AD subjects have significantly fewer viable precursor cells in the hippocampus compared with age‐matched healthy control subjects. However, the viable precursor cells that remain in AD and age‐matched healthy control brain specimens can be induced to differentiate[15]. To facilitate or mimic the natural compensatory effect in AD, two kinds of cells are considered: endogenous and exogenous stem cells.

2.2.1 Endogenous stem cells

Some therapeutic approaches have focused on augmenting the brain’s normal endogenous reaction to injury. Multiple pathways have been used to induce neurogenesis, including those triggered by granulocyte colony‐stimulating factor (G‐CSF), stromal cell‐derivedfactor‐1a (SDF‐1α), and insulin growth factor (IGF‐1). Alternative mechanisms of increasing endogenous NSC proliferation include anti‐inflammatory drugs (e.g., indomethacin), non‐coding RNA, hormones such as erythropoietin, allopregnanolone (Apα), and fluoxetine among others[16–21].

The distribution of G‐CSF and G‐CSF receptor does not substantially differ between AD and control brains, even in the hippocampus[22]. However, this does not diminish the effect of G‐CSF in AD treatment. G‐CSF application was shown to improve memory and neurobehavior in an amyloid‐β induced experimental model of AD[23, 24]. G‐CSF also could decrease the brain amyloid burden[25].

SDF‐1α is an effective adjuvant for inducing endogenous bone marrow‐derived hematopoietic progenitor cells, which are mobilized by G‐CSF, to migrate into the brain. These two treatments can act synergistically to produce a therapeutic effect[26].

Glucagon‐like peptide 1 (GLP1) is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and a GLP1 analogue, liraglutide, can increase cell proliferation and differentiation into neurons in an AD mouse model[27].

Recent studies have proposed that chronic treatment with antidepressants increases neurogenesis in the adult hippocampus. Chang et al.[28]showed dose‐dependent effects of fluoxetine, a common antidepres‐sant, on the proliferation and neural differentiation of fetal derived NSCs. Fluoxetine, even at nanomolar concentrations, stimulated proliferation and differen‐tiation in NSCs. In addition, fluoxetine exhibits protective effects against cell death induced by Aβ42. Chadwick et al.[29]showed that amitriptyline, another common antidepressant, mediated cognitive enhancement in aged AD mice and is associated with neurogenesis and neurotrophic activity.

2.2.2 Exogenous stem cells

Many exogenous cell lines have been tested for AD therapy, particularly in animal models[30].

(1) Embryonic stem cells (ESCs)

Transplantation of mouse ESC‐derived NSCs follow‐ing the commitment to a cholinergic cell phenotype can promote behavioral recovery in a rodent model of AD. The absence of tumor formation indicates that ESCs may be safe for transplantation[31].

(2) Mesenchymal stem cells (MSCs)

MSCs were identified for the first time in 1974 by Friedenstein et al.[32]Due to their capacity to differentiate into mesenchymal cells such as osteoblasts, adipocytes, and chondroblasts, they were termed MSCs.

In AD animal models, MSCs have been shown to be beneficial for increasing neurogenesis and neuronal differentiation, enhancing Aβ clearance, inhibiting cell death, and improving clinical symptoms, including memory impairment. MSCs increase hippocampal neurogenesis, neuronal differentiation, and the for‐mation of neurites in AD animal’s model[33–35].

MSCs can inhibit cell apoptosis and cell death caused by either Aβ or tau, which is accompanied by memory improvement[36]. MSCs have the capacity to clear Aβ but not tau. One possible way in which Aβ may be cleared is by enhancing autophagy functions[37]. Recently, it was shown MSCs could reduce plaque size[38]. Most importantly, MSCs can promote the reduction of Aβ and improve synaptic transmission both in AD[39]and in pre‐dementia AD mice[40], which indicates that MSCs may exert their effects in different stages of AD.

Adipose tissue‐derived mesenchymal stem cells are considered good candidates for stroke treatment because of their abundance and ease of harvesting without the need for invasive surgery on healthy donors. Transplantation of human adipose tissue‐derived MSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with the recovery of acetylcholine levels in brain tissues, which was accomplished by enhancing the concentrations of brain‐derived neurotrophic factor (BDNF), nerve growth factor (NGF)[41], and vascular endothelial growth factor (VEGF)[42].

(3) Neural stem/progenitor cells (NSPCs)

Aβ increases NSPC activity[43], which may be a natu‐ral reaction against toxicity induced by AD. After conditional neuronal ablation in the hippocampus, NSPCs survived, migrated, differentiated, and, most significantly, improved memory after being transplanted into the brain[44]. This may be due to the attenuation of inflammatory activity induced by intrahippocampalpeptide injection[45]and was shown to improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic mouse model of AD[46]. After NSPCs were bilaterally transplanted into the hippocampal regions of APP/PS1 mice, spatial learning and memory functions were improved without altering Aβ pathology. The expression of BDNF was related to increases in cognitive function[47]and improved the effects of NSPCs at the same time[48]. Most importantly, transplanted NSPCs can differentiate into cholinergic neurons in a rat AD model[49].

NSPC transplantation did not have a significant impact on Aβ plaques in AD mice, but the tropism of engrafted NSPCs may be able to replace lost or damaged cells, reverse the course of AD in mice to some extent[50], possibly reduce tau accumulation[51], or improve the survival of aged and degenerating neurons[52].

(4) Umbilical cord blood cells and related cells

Human umbilical cord blood mononuclear cells (hUCB‐MSCs) reduce hippocampal apoptosis induced by Aβ treatment in vitro. Moreover, studies in an acute AD mouse model demonstrated cognitive rescue with restoration of learning and memory function[53, 54]. The therapeutic effects may be mediated through the modulation of neuroinflammation[55].

Human placenta amniotic membrane‐derived MSCs might show significant long‐lasting improvement in AD pathology and memory function via immuno‐modulation. hUCB‐MSCs demonstrated considerable extension of life and ameliorated AD in transgenic mice[56]. Additionally, this type of cell also correlates with decreases in cognitive impairment, Aβ levels/β‐amyloid plaques, amyloidogenic APP processing, and reactive microgliosis after treatment[57, 58]with a paracrine mechanism[59].

(5) Induced pluripotent stem cells (iPSCs)

Currently, a number of options exist to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of iPSCs has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologously and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary.

Neuronal precursors with the cholinergic neuron phenotype derived from human iPSCs survived in the APP mouse hippocampus and ameliorated spatial memory loss[60]. iPSCs, derived from the dermal fibroblasts of AD patients that differentiated into cholinergic neurons, might be a promising novel tool for disease modeling and drug discovery for the sporadic[61]and familial forms of AD[62].

2.3 The rationality for cell therapy in AD

Thus far, plentiful evidence has demonstrated the involvement of impaired neurogenesis/stem cells involved in the pathophysiology of AD, which facilitate cell therapy as a potential treatment consideration in AD.

(1) Impaired neurogenesis in the SVZ has been found in early AD[63, 64].

(2) Aβ impairs the proliferation and neuronal differ‐entiation of neuronal precursor cells and contributes to the depletion of neurons and cognitive impairment in AD[65]. Amyloid precursor protein (APP), especially APP possessing the protease inhibitor domain, regulates the growth of neuronal precursor cells during develop‐ment of the nervous system[66].

(3) Either a wild‐type or a mutant presenilin (PS)‐1 transgene can reduce the number of neural pro‐genitors in the dentate gyrus. Additionally, there is some evidence demonstrating a compensatory increase in neurogenesis after PS‐1 mutation, which represents familial AD pathogenesis[67]. Taken together, these indicate that the inherited form of AD is related with impaired endogenous stem cells[68].

(4) In separate work, it has been demonstrated that the deafferented hippocampus provided a suitable microenvironment for the survival and neuronal differentiation of neural progenitors[69].

(5) Finally, neurogenesis was shown to decrease with age, but persist throughout life[70].

The above data suggests that the pathophysiology of AD is involved in the neurogenesis of the hippocampus and related structures, and hence it is reasonable to consider cell therapy for AD treatment.However, there are still many more mechanisms to be clarified and require further research to be identified.

2.4 The mechanism of cell therapy in AD

The cell types that have been most tested in AD are ESCs, NSPCs, MSCs, and iPSCs. In general, these cell types have been shown to be beneficial for increasing neurogenesis and neuronal differentiation, enhancing Aβ clearance, inhibiting cell death, improving acetylcholine levels, and improving clinical symptoms, including memory and visuospatial impairment.

(1) Increased neurogenesis

In AD models, stem cells have been shown to increase neurogenesis, neuronal differentiation, and the formation of neurites, particularly in the hippocampus. These outcomes may be mediated by enhancement of the Wnt signaling pathway[34, 37].

(2) Decreased neuroinflammation

AD is characterized by the deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, leading to neuronal dysfunction and death. Treatment with NSPCs significantly improved cognitive deficits and was accompanied by the attenuation of inflammatory injury[71].

(3) Enhancing endogenous synaptogenesis

Human neural stem cells improve cognition and promote synaptic growth in transgenic models of AD[72].

(4) Inhibition of cell apoptosis and cell death

MSCs can inhibit cell apoptosis and cell death caused by either Aβ or tau[34, 37], which are accompanied by memory improvement[73].

(5) Clearance of protein aggregates

Aβ is considered the main pathogenetic factor of AD. According to the amyloid cascade hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stages of the disease. Stem cells have the capacity to clear Aβ, either in soluble or plaque form[39, 40, 74].

(6) Increased trophic factors

Neurotrophins (NTFs) are secreted peptides that act as growth factors promoting the differentiation, growth, and maintenance of developing neurons, the survival of adult mature neurons, and play a central role in synaptic plasticity. NTFs have been more extensively studied thanks to their ability to prevent the gradual loss of basal forebrain cholinergic neurons and atrophy observed in healthy aging and AD. In this context, NGF and BDNF seem to play prominent roles. Furthermore, AD animal models have provided evidence that a shortage of NGF supply may induce an AD‐like syndrome[75]. Human adipose tissue‐derived MSCs could enhance the concentrations of BDNF and NGF, which could lead to an improvement in cognitive function[41]. Another group have shown that MSCs significantly attenuated memory deficits and neuropathology, by up‐regulating cytokine interleukin (IL)‐10 and VEGF[42].

(7) Induction of acetylcholine production in AD

Increasing the acetylcholine level is a crucial part of current therapeutic approaches for AD. In neurorestorative treatment, two methods can be used to increase the acetylcholine level: bioengineering and cell therapy. For the latter, several cell types have been shown to have the potential to differentiate into cholinergic cell phenotypes. Transplanted NSCs were shown to differentiate into cholinergic neurons in a rat AD model[49]. Transplantation of mouse ESC‐derived neuronal precursor cells, following commitment to a cholinergic cell phenotype, was able to promote behavioral recovery in a rodent model of AD[31].

In fact, transplanted cells modulate diverse AD pathologies and rescue impaired memory via multiple mechanisms in an AD model[76, 77].

2.5 The therapeutic window for AD

MSCs can promote the reduction of Aβ and the improvement of synaptic transmission, both in AD mice and in pre‐dementia AD mice, which indicates that MSCs may exert their effects at different stages of AD. However, the optimal stage of the disease for stem cell transplantation to have a therapeutic effect is yet to be determined. Transplantation of NSPCs into the brain of a 12‐month‐old transgene animal model markedly improved both cognitive impairments and neuropathological features by reducing β‐amyloid processing and up‐regulating clearance of β‐amyloid, secretion of anti‐inflammatory cytokines, endogenous neurogenesis, as well as synapse formation. In contrast, stem cell transplantation did not recover cognitivedysfunction and β‐amyloid neuropathology in the same transgene mice aged 15 months when the memory loss is manifest. Overall, this study underscores that stem cell therapy at the optimal time frame is crucial to obtain maximal therapeutic effects that can restore functional deficits or stop the progression of AD[78].

Furthermore, Aβ1‐42 induces hypometabolism in human stem cell‐derived neuronal and astrocytic networks[79], which suggests that a maximal therapeutic dose will be necessary to avoid the negative effects of Aβ to the transplanted cells.

2.6 Extracellular vesicles (EVs) and exosomes of stem cells: A potential alternative method for stem cells

The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in AD. However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretions. While stem and progenitor cells secrete many therapeutic molecules, none of these molecules alone or in combination could duplicate the functional effects of stem cell transplantation. Recently, it was reported that EVs could replicate the therapeutic effects of stem cell transplantation.

Based on observations reported thus far, the prevailing hypothesis is that stem cell EVs exert their therapeutic effects by transferring biologically active molecules such as proteins, lipids, mRNA, and microRNA from stem cells to injured or diseased cells. They are both primarily vehicles for intercellular communication[80, 81].

3 Conclusions

Although much is known about the neurobiology of AD, very few conventional therapies are available to arrest or slow the disease. There is an urgent need for novel therapeutic approaches for AD. Translating neurorestorative strategies with positive preclinical results for AD into clinical studies has allowed patients to receive clinical neurorestoration to a certain extent, via medicines, cell therapy, neuromodulation, neurorehabilitation, and combined therapies. Cell‐based neurorestorative strategies are currently promising for AD. To gain better neurorestorative effect, early intervention neurorestorative strategies for AD should be recommended because dementia and other clinical presentations occur well after the pathological findings in AD. In the future, there should be greater encourage‐ment to translate effective preclinical neurorestorative strategies to clinical practice as quickly as possible.

Conflict of interests

The authors have no financial interest to disclose regarding the article.

Reference

[1] Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 2015, 11(3): 332–384.

[2] Drachman DA. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement 2014, 10(3): 372–380.

[3] Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 2012, 8(1): 1–13.

[4] Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol 2012, 71(5): 362–381.

[5] Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and cholinesterase inhibitors: Complementary mechanisms in the treatment of Alzheimer’s disease. Neurotox Res 2013, 24(3): 358–369.

[6] Muoio V, Persson PB, Sendeski MM. The neurovascular unitconcept review. Acta Physiol (Oxf) 2014, 210(4): 790–798.

[7] Baloyannis SJ, Baloyannis IS. The vascular factor in Alzheimer’s disease: A study in Golgi technique and electron microscopy. J Neurol Sci 2012, 322(1-2): 117–121.

[8] Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 2009, 118(1): 103–113.

[9] Terry AV Jr., Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003, 306(3): 821–827.

[10] Altman J. Are new neurons formed in the brains of adult mammals? Science 1962, 135(3509): 1127–1128.

[11] Altman J. Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec 1963, 145: 573–591.

[12] Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965, 124(3): 319–335.

[13] Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 1969, 137(4): 433–457.

[14] Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 1998, 4(11): 1313–1317.

[15] Lovell MA, Geiger H, Van Zant GE, Lynn BC, Markesbery WR. Isolation of neural precursor cells from Alzheimer’s disease and aged control postmortem brain. Neurobiol Aging 2006, 27(7): 909–917.

[16] Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, et al. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 2002, 16(6): 601–603.

[17] Koren J, 3rd, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA. Chaperone signalling complexes in Alzheimer’s disease. J Cell Mol Med 2009, 13(4): 619–630.

[18] Choi SS, Lee SR, Kim SU, Lee HJ. Alzheimer’s disease and stem cell therapy. Exp Neurobiol 2014, 23(1): 45–52.

[19] Wilhelmus MM, de Waal RM, Verbeek MM. Heat shock proteins and amateur chaperones in amyloid-Beta accumulation and clearance in Alzheimer’s disease. Mol Neurobiol 2007, 35(3): 203–216.

[20] Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R, Murata S, Tanaka K, Takashima A. In vivo evidence of CHIP up-regulation attenuating tau aggregation. J Neurochem 2005, 94(5): 1254–1263.

[21] Jinwal UK, O’Leary JC, Borysov SI, Jones JR, Li Q, Koren J, Abisambra JF, Vestal GD, Lawson LY, Johnson AG, Blair LJ, Jin Y, Miyata Y, Gestwicki JE, Dickey CA. Hsc70 rapidly engages tau after microtubule destabilization. J Biol Chem 2010, 285(22): 16798–16805.

[22] Ridwan S, Bauer H, Frauenknecht K, Hefti K, von Pein H, Sommer CJ. Distribution of the hematopoietic growth factor G-CSF and its receptor in the adult human brain with specific reference to Alzheimer’s disease. J Anat 2014, 224(4): 377–391.

[23] Prakash A, Medhi B, Chopra K. Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-beta induced experimental model of Alzheimer’s disease. Pharmacol Biochem Behav 2013, 110: 46–57.

[24] Tsai KJ, Tsai YC, Shen CK. G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J Exp Med 2007, 204(6): 1273–1280.

[25] Sanchez-Ramos J, Song S, Sava V, Catlow B, Lin X, Mori T, Cao C, Arendash GW. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer’s mice. Neuroscience 2009, 163(1): 55–72.

[26] Shin JW, Lee JK, Lee JE, Min WK, Schuchman EH, Jin HK, Bae JS. Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer’s disease mouse model. Stem Cells 2011, 29(7): 1075–1089.

[27] Parthsarathy V, Holscher C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoS One 2013, 8(3): e58784.

[28] Chang KA, Kim JA, Kim S, Joo Y, Shin KY, Kim HS, Suh YH. Therapeutic potentials of neural stem cells treated with fluoxetine in Alzheimer’s disease. Neurochem Int 2012, 61(6): 885–891.

[29] Chadwick W, Mitchell N, Caroll J, Zhou Y, Park SS, Wang L, Becker KG, Zhang Y, Lehrmann E, Wood WH, Martin B, Maudsley S. Amitriptyline-mediated cognitive enhancement in aged 3xTg Alzheimer’s disease mice is associated with neurogenesis and neurotrophic activity. PLoS One 2011, 6(6): e21660.

[30] Kakio A, Nishimoto SI, Yanagisawa K, Kozutsumi Y, Matsuzaki K. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid. J Biol Chem 2001, 276(27): 24985–24990.

[31] Moghadam FH, Alaie H, Karbalaie K, Tanhaei S, Nasr Esfahani MH, Baharvand H. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Differentiation 2009, 78(2-3): 59–68.

[32] Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974, 17(4): 331–340.

[33] Oh SH, Kim HN, Park HJ, Shin JY, Lee PH. Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the wnt signaling pathway in an Alzheimer’s disease model. Cell Transplant 2015, 24(6): 1097–1109.

[34] Zilka N, Zilkova M, Kazmerova Z, Sarissky M, Cigankova V, Novak M. Mesenchymal stem cells rescue the Alzheimer’s disease cell model from cell death induced by misfolded truncated tau. Neuroscience 2011, 193:330–337.

[35] Khairallah MI, Kassem LA, Yassin NA, El Din MA, Zekri M, Attia M. The hematopoietic growth factor “erythropoietin”enhances the therapeutic effect of mesenchymal stem cells in Alzheimer’s disease. Pak J Biol Sci 2014, 17(1): 9–21.

[36] Lee HJ, Lee JK, Lee H, Shin JW, Carter JE, Sakamoto T, Jin HK, Bae JS. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer’s disease. Neurosci Lett 2010, 481(1): 30–35.

[37] Shin JY, Park HJ, Kim HN, Oh SH, Bae JS, Ha HJ, Lee PH. Mesenchymal stem cells enhance autophagy and increase betaamyloid clearance in Alzheimer disease models. Autophagy 2014, 10(1): 32–44.

[38] Naaldijk Y, Jager C, Fabian C, Leovsky C, Bluher A, Rudolph L, Hinze A, Stolzing A. Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol 2016.

[39] Lee JK, Jin HK, Bae JS. Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci Lett 2009, 450(2): 136–141.

[40] Bae JS, Jin HK, Lee JK, Richardson JC, Carter JE. Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer’s disease. Curr Alzheimer Res 2013, 10(5): 524–531.

[41] Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, Kim D, Choi EK, Choi KC, Kim SU, Kang SK, Ra JC, Kim YB. Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res 2013, 91(5): 660–670.

[42] Kim S, Chang KA, Kim J, Park HG, Ra JC, Kim HS, Suh YH. The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PLoS One 2012, 7(9): e45757.

[43] Diaz-Moreno M, Hortiguela R, Goncalves A, Garcia-Carpio I, Manich G, Garcia-Bermudez E, Moreno-Estelles M, Eguiluz C, Vilaplana J, Pelegri C, Vilar M, Mira H. Abeta increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiol Aging 2013, 34(11): 2623–2638.

[44] Yamasaki TR, Blurton-Jones M, Morrissette DA, Kitazawa M, Oddo S, LaFerla FM. Neural stem cells improve memory in an inducible mouse model of neuronal loss. J Neurosci 2007, 27(44): 11925–11933.

[45] Ryu JK, Cho T, Wang YT, McLarnon JG. Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. J Neuroinflammation 2009, 6: 39.

[46] Zhang W, Wang PJ, Sha HY, Ni J, Li MH, Gu GJ. Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease. Mol Neurobiol 2014, 50(2): 423–437.

[47] Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA 2009, 106(32): 13594–13599.

[48] Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL. BDNF improves the effects of neural stem cells on the rat model of Alzheimer’s disease with unilateral lesion of fimbria-fornix. Neurosci Lett 2008, 440(3): 331–335.

[49] Xuan AG, Luo M, Ji WD, Long DH. Effects of engrafted neural stem cells in Alzheimer’s disease rats. Neurosci Lett 2009, 450(2): 167–171.

[50] Zhang W, Wang PJ, Gu GJ, Li MH, Gao XL. Effects of neural stem cells transplanted into an animal model of Alzheimer disease on Abeta plaques. Zhonghua Yi Xue Za Zhi 2013, 93(45): 3636–3639.

[51] Kern DS, Maclean KN, Jiang H, Synder EY, Sladek JR Jr., Bjugstad KB. Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice. Cell Transplant 2011, 20(3): 371–379.

[52] Wu S, Sasaki A, Yoshimoto R, Kawahara Y, Manabe T, Kataoka K, Asashima M, Yuge L. Neural stem cells improve learning and memory in rats with Alzheimer’s disease. Pathobiology 2008, 75(3): 186–194.

[53] Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells 2010, 28(2): 329–343.

[54] Yang H, Xie Z, Wei L, Yang S, Zhu Z, Wang P, Zhao C, Bi J. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloidbeta deposition in an AbetaPP/PS1 transgenic mouse model. Stem Cell Res Ther 2013, 4(4):76.

[55] Lee HJ, Lim IJ, Park SW, Kim YB, Ko Y, Kim SU. Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction. Cell Transplant 2012, 21(11): 2487–2496.

[56] Ende N, Chen R, Ende-Harris D. Human umbilical cord blood cells ameliorate Alzheimer’s disease in transgenic mice. J Med 2001, 32(3-4): 241–247.

[57] Darlington D, Deng J, Giunta B, Hou H, Sanberg CD, Kuzmin-Nichols N, Zhou HD, Mori T, Ehrhart J, Sanberg PR, Tan J. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-beta-associated neuropathology in Alzheimer mice. Stem Cells Dev 2013, 22(3): 412–421.

[58] Nikolic WV, Hou H, Town T, Zhu Y, Giunta B, Sanberg CD, Zeng J, Luo D, Ehrhart J, Mori T, Sanberg PR, Tan J. Peripherally administered human umbilical cord blood cellsreduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells Dev 2008, 17(3): 423–439.

[59] Kim KS, Kim HS, Park JM, Kim HW, Park MK, Lee HS, Lim DS, Lee TH, Chopp M, Moon J. Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model. Neurobiol Aging 2013, 34(10): 2408–2420.

[60] Fujiwara N, Shimizu J, Takai K, Arimitsu N, Saito A, Kono T, Umehara T, Ueda Y, Wakisaka S, Suzuki T, Suzuki N. Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors derived from human iPS cells. Neurosci Lett 2013, 557 Pt B: 129–134.

[61] Ooi L, Sidhu K, Poljak A, Sutherland G, O'Connor MD, Sachdev P, Munch G. Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease. J Neural Transm 2013, 120(1): 103–111.

[62] Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 2011, 20(23): 4530–4539.

[63] Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice. J Neurosci Res 2010, 88(10): 2103–2117.

[64] Rodriguez JJ, Jones VC, Verkhratsky A. Impaired cell proliferation in the subventricular zone in an Alzheimer’s disease model. Neuroreport 2009, 20(10): 907–912.

[65] Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid betapeptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem 2002, 83(6): 1509–1524.

[66] Hayashi Y, Kashiwagi K, Ohta J, Nakajima M, Kawashima T, Yoshikawa K. Alzheimer amyloid protein precursor enhances proliferation of neural stem cells from fetal rat brain. Biochem Biophys Res Commun 1994, 205(1): 936–943.

[67] Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol 2005, 167(1): 151–159.

[68] Wen PH, Shao X, Shao ZP, Hof PR, Wisniewski T, Kelley K, Friedrich Jr. VL, Ho L, Pasinetti GM, Shioi JC, Robakisa NK, Eldera GA. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis 2002, 10(1): 8–19.

[69] Zhang X, Jin G, Tian M, Qin J, Huang Z. The denervated hippocampus provides proper microenvironment for the survival and differentiation of neural progenitors. Neurosci Lett 2007, 414(2): 115–120.

[70] Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996, 16(6): 2027–2033.

[71] Zhang Q, Wu HH, Wang Y, Gu GJ, Zhang W, Xia R. Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer’s disease. J Neurochem 2015.

[72] Ager RR, Davis JL, Agazaryan A, Benavente F, Poon WW, LaFerla FM, Blurton-Jones M. Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer’s disease and neuronal loss. Hippocampus 2015, 25(7): 813–826.

[73] Lee JK, Jin HK, Bae JS. Bone marrow-derived mesenchymal stem cells attenuate amyloid beta-induced memory impairment and apoptosis by inhibiting neuronal cell death. Curr Alzheimer Res 2010, 7(6): 540–548.

[74] Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010, 68(4): 521–534.

[75] Calissano P, Matrone C, Amadoro G. Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Dev Neurobiol 2010, 70(5): 372–383.

[76] Lee IS, Jung K, Kim IS, Lee H, Kim M, Yun S, Hwang K, Shin JE, Park KI. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegener 2015, 10: 38.

[77] Lilja AM, Malmsten L, Rojdner J, Voytenko L, Verkhratsky A, Ogren SO, Nordberg A, Marutle A. Neural stem cell transplant-induced effect on neurogenesis and cognition in Alzheimer Tg2576 mice is inhibited by concomitant treatment with amyloid-lowering or cholinergic alpha7 nicotinic receptor drugs. Neural Plast 2015, 2015: 370432.

[78] Kim JA, Ha S, Shin KY, Kim S, Lee KJ, Chong YH, Chang KA, Suh YH. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer’s disease mouse model. Cell Death Dis 2015, 6: e1789.

[79] Tarczyluk MA, Nagel DA, Rhein Parri H, Tse EH, Brown JE, Coleman MD, Hill EJ. Amyloid beta 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks. J Cereb Blood Flow Metab 2015, 35(8): 1348–1357.

[80] Burke J, Kolhe R, Hunter M, Isales C, Hamrick M, Fulzele S. Stem cell-derived exosomes: A potential alternative therapeutic agent in orthopaedics. Stem Cells Int 2016, 2016:5802529.

[81] Zhang B, Yeo RW, Tan KH, Lim SK. Focus on extracellular vesicles: Therapeutic potential of stem cell-derived extracellular vesicles. Int J Mol Sci 2016, 17(2): 174.