Hayashi et al.

Journal of Biomedical Science (2020) 27:29

https://doi.org/10.1186/s12929-020-0622-x

REVIEW Open Access

Effects of neural stem cell transplantation

in Alzheimer’s disease models
Yoshihito Hayashi1,2†, Huan-Ting Lin3†, Cheng-Che Lee1 and Kuen-Jer Tsai1,4,5*

Abstract
Currently there are no therapies for treating Alzheimer’s disease (AD) that can effectively halt disease progression.
Existing drugs such as acetylcholinesterase inhibitors or NMDA receptor antagonists offers only symptomatic benefit.
More recently, transplantation of neural stem cells (NSCs) to treat neurodegenerative diseases, including AD, has been
investigated as a new therapeutic approach. Transplanted cells have the potential to replace damaged neural circuitry
and secrete neurotrophic factors to counter symptomatic deterioration or to alter lesion protein levels. However, since
there are animal models that can recapitulate AD in its entirety, it is challenging to precisely characterize the positive
effects of transplanting NSCs. In the present review, we discuss the types of mouse modeling system that are available
and the effect in each model after human-derived NSC (hNSC) or murine-derived NSC (mNSC) transplantation. Taken
together, results from studies involving NSC transplantation in AD models indicate that this strategy could serve as a
new therapeutic approach.
Keywords: Alzheimer’s disease, Neural stem cell, Synaptogenesis, Neurogenesis, Inflammation, Cognitive impairment,
Cell therapy

Introduction the relationship of pathological proteins in AD develop-

Alzheimer’s disease (AD) is a common progressive neuro- ment remain uncertain. Several studies have used AD
degenerative disorder that has been studied by scientists for mouse models to address some of these questions. How-
over a century. It was first named by Alois Alzheimer in ever, their physiological relevance to humans is question-
1906 [1]. The symptoms of AD include memory loss and able, since animal models have yet to fully recapitulate
cognitive impairment caused by significant losses in the human AD. The dominant hypothesis for AD develop-
number of neurons in the cortical and subcortical regions ment is amyloid-beta (Aβ) aggregation in the extracellular
[2]. A large proportion of the elderly population suffers region and neurofibrillary tangles caused by tau hyperpho-
from AD, exacerbating the economic burden associated sphorylation in the intracellular space. These irregular
with an ageing society. Indeed, the number of patients con- protein aggregations are followed by neuron degeneration
tinues to grow and is estimated to double or triple within and synaptic loss. Notably, patients with early on-set AD
the next few decades [3]. Therefore, optimizing the treat- carry only the Aβ mutation, not the tau mutation [4]. In
ment for AD is of great priority. order to closely mimic the intracellular and extracellular
microenvironment of patients with AD, it is necessary to
introduce additional mutations to genes encoding amyloid
Models of Alzheimer’s disease precursor protein (APP) and presenilin-1 (PS1), as well as
Although the volume of studies that has been undertaken an extra tau mutation into triple-transgenic (3xTg) mice.
is considerable, elements of the disease mechanism and This extra tau mutation in 3xTg mice has reduced the
reliability of the model. Other alternatives include the
* Correspondence: [email protected]
†
Yoshihito Hayashi and Huan-Ting Lin contributed equally to this work. Tg2576, APP/PS1 and 5xfAD mouse models, but in these
1
Institute of Clinical Medicine, College of Medicine, National Cheng Kung instances only Aβ aggregation is observed but no neuro-
University, Tainan, Taiwan fibrillary tangles. Moreover, in mice models, no significant
4
Research Center of Clinical Medicine, National Cheng Kung University
Hospital, College of Medicine, National Cheng Kung University, Tainan, neuron loss or cognitive dysfunction occurs before Aβ
Taiwan deposition as observed in actual AD patients [5, 6]. It
Full list of author information is available at the end of the article

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 2 of 11

remains unclear the extent to which these discrepancies in heartbeats and severe gastrointestinal problems compared
observation are attributable to the different genetic com- with single drug treatment [12]. Thus, it is unclear how
position of these mouse models of AD. valuable such a palliative drug-based approach can be.
More recently, induced pluripotent stem cells (iPSCs) New drugs that target the pathological protein itself—so-
have been derived from patients with AD and established called anti-amyloids medication —are experiencing diffi-
as a disease model. Numerous studies in AD-iPSCs have culties in clinical trials [13] as the effects appear independ-
reported that levels of toxic Aβ and hyperphosphorylated ent from symptomatic improvement [14]. Meanwhile,
tau protein are dramatically elevated in differentiated neur- researchers are investigating the potential use of vaccina-
onal cells. However, no Aβ plaques or neurofibrillary tan- tions to counter plaque formation, as well as more ad-
gles form. This may be due to limitations in the culture vanced techniques that facilitates early AD diagnosis,
system and that differentiated cells have yet to reach ma- which could be especially beneficial to patients before they
ture status. Furthermore, AD-iPSC genotypes vary amongst enter the more severe late stages of the disease [15].
donors, thus differentiated cells from one individual alone
is insufficient to model the abnormal cellular network in Therapeutic effect of neural stem cell
AD in its entireity. Additionally, the pathological hallmarks transplantation
of AD are expressed earlier in AD-iPSCs than in AD pa- Neural stem cells
tients thus similar to existing mouse models, recapitulation As a novel therapeutic strategy, neural stem cell (NSC)
of AD is incomplete. Combined with the wide range of transplantation, which target both neuron networks and
both genomic and phenotypical variations in iPSCs, the pathological proteins, produces beneficial result in be-
suitability of their application as a modelling system remain havior and microenvironment. In brief, most traditional
debatable. As such, fair comparisons can only be made drug therapies act merely upon the microenvironment.
using an isogenic control, which will require complex gene As multipotent stem cells, NSCs can self-renew and dif-
editing techniques to correct the mutations [7]. ferentiate into various cell types, such as neurons and
glial cells [16, 17]. NSCs can be collected from brain tis-
Current treatment of AD sue, genetically reprogrammed from somatic cells [18,
Reducing Aβ levels has been the dominant treatment strat- 19], or even differentiated from embryonic stem cells
egy in development to halt, retard or even reverse the pro- (ESCs) and iPSCs [17, 20]. In adults, NSCs are localized
gression of AD pathology. However, there are no Food and in the sub-ventricular zone (SVZ) and hippocampus [21,
Drug Administration (FDA)-approved drugs targeted at re- 22]. As with drug therapy, many studies have suggested
ducing Aβ levels. In fact, no new Alzheimer’s drug therap- that NSC transplantation improves cognitive behaviour in
ies have been approved for almost two decades, and only animal models of AD [23], Parkinson’s disease [24, 25]
three types of cholinesterase inhibitors, one N-methyl-d- Huntington’s disease [26, 27], amyotrophic lateral sclerosis
aspartate (NMDA) receptor antagonist, and one combined [28] and other neurodegenerative diseases. After trans-
drug therapy (memantine plus donepezil) are currently ap- plantation, NSCs differentiate into neurons and/or glial
proved for clinical use [8]. Donepezil, rivastigmine, and cells and release trophic factors. Asymmetric NSC division
galantamine are cholinesterase inhibitors that reduce generates different cell types that replace damaged neu-
acetylcholinesterase activity and thus prevent insufficient rons [29, 30] and the neurotrophic factors released from
acetylcholine levels in the synaptic region. Preserving both differentiated cells and stem cells are related to rapid
acetylcholine levels allows effective neuronal function des- differentiation [31] and play a significant role in neuropro-
pite pathological protein aggregation. However, excess ex- tection to rescue synaptic density [32–34]. Secretion of
citatory stimulation, especially that caused by high neurotrophic factors and cell restoration has been shown
glutamate levels, can lead to an excitotoxic microenviron- to improve individual memory function [35, 36]. Further-
ment in the synaptic region through invasive calcium in- more, modified NSCs overexpress Aβ degrading-enzyme
flux. This may eventually damage or even lead to neuronal [37], which reduces Aβ aggregation and improves synaptic
cell death [9]. Many studies have shown that such hyper- density. Novel drugs that are currently in development
stimulation is closely associated with oversensitive NMDA have shifted their focus to targeting these mechanisms to
and/or AMPA receptors. The drug memantine, which is halt or reverse disease progression [38]. Considering that
an NMDA receptor antagonist, acts to offset this harmful NSCs can restore damaged cells, reduce Aβ aggregation,
Ca2+ influx into neurons [10]. Finally, combination therapy ameliorate AD pathology as well as restoring neuronal cell
using memantine and donepezil combines the effects of a populations [32, 34, 39], NSC therapy is a promising and
cholinesterase inhibitor and an NMDA-receptor antagonist flexible novel therapeutic strategy for targeting the pri-
(Fig. 1). This combined therapy appears to be more effect- mary cause of AD. Unfortunately the efficacy compared
ive [11]. However, it also carries greater possibility of oc- with placebo groups has been inconsistent, not to mention
currence of more serious side effects such as seizure, slow several ethical questions and disagreements on how they
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 3 of 11

Fig. 1 The mechanisms of the respective drugs. Acetylcholinesterase inhibitors (galantamine, rivastigmine and donepezil) enhance the activity of
neuro-message transduction by preventing acetylcholine degradation (1,2,3). NMDA receptor antagonists (memantine) compete with glutamate
in binding to the NMDA receptor to inhibit Ca2+ influx into the postsynapse (4,5). These drugs have little effect on amyloid-beta production and
aggregation, synaptogenesis, and neurogenesis yet they rescue cognitive impairment

should be correctly handled [40]. Nonetheless, stem cell lineages alone contributes little to cognitive recovery, and
therapy is certainly one of the most promising therapeutic that hCNS-SC transplantation may serve to reverse the
strategies in development. symptoms only [43] (Table 1).
Interestingly, transplanting mNSCs instead of hNSCs
Different effects of NSC transplantation in Alzheimer’s produced similar results in the 3xTg mice model. In a
models study by Mathew et al., both neurotrophin and brain-
Human-derived NSC vs murine-derived NSC in 3xTg mice derived neurotrophic factor (BDNF) secreted from trans-
The 3xTg mouse is a triple-transgenic AD animal model planted NSCs enhanced synaptic density and rescued cog-
established by Oddo et al. in 2003. The model carries three nitive impairment. However, this result was again
mutations related to familial Alzheim’s disease (FAD): APP independent from Aβ and tau levels. In the same study,
Swedish, MAPT P301L, and PSEN1 M146 V. The 3xTg BDNF was shown to support axon growth in vitro thus in-
mouse model is the first transgenic AD model to express creasing synaptic density [23]. Furthermore, cell regener-
both Aβ aggregation and neurofibrillary tangles from ation and/or repair triggered by NSCs improves cognitive
hyperphosphorylated tau protein. Intracellular and extracel- function by ameliorating neuronal networks [44], so NSCs
lular Aβ aggregation is observed at 4 months and 6 months are closely associated with improved behavioural perform-
of age respectively, while cognitive impairment starts at 4 ance in the 3xTg animal model. To further evaluate the
months and tau is first observed at 12 months [41, 42]. impact of NSCs under conditions of pathological protein
In 2015, Ager et al. first introduced human central ner- alteration, modified NSCs carrying Neprilysin (NEP) were
vous system stem cells (hCNS-SCs) into 3xTg mice. The introduced into 3xTg mice. Viral vector-delivered NEP
transplanted hCNS-SCs differentiated into NSCs and then was then compared with NSC-delivered NEP and found
into immature neurons and glial cells, which improved to be less widely distributed throughout the brain. More-
synaptic density. Although the levels of Aβ and tau pro- over, peripheral NEP introduction had less effect in clear-
teins remained unchanged, both the Morris-water-maze ing Aβ in the brain. These results suggest that NSCs can
and novel object recognition tests indicated improved act as an effective NEP-delivery vehicle. It follows that the
memory consolidation. In contrast, no significant im- combination of NEP delivery and NSC transplantation
provement in learning ability was observed after hCNS- further improves synaptic density by decreasing Aβ levels,
SCs transplantation. Although encouraging, these results and that NSCs may be a promising AD therapeutic strat-
suggest that specific differentiation into neuronal cell egy [45, 46] (Table 1).
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 4 of 11

Table 1 Summary of factors and effects after neural stem cell transplantation in 3xTg mice
NSC Region Factor Effect Not-shown Aβ/tau Ref
3xTg mice
hCNS-SC Hippocampus ↑immature neuron ↑endogenous ・The relation of endogenous × [43]
↑immature glia cell synaptogenesis synaptogenesis and hCNS-SC
↑synaptic density ・Role of neurotrophic factor
GFP tg mice relative to Bregma of: ↑BDNF ↑synaptic density ・Axonal growth in vivo × [23]
AP:_ 2.06, ML:_1.75, DV:_1.75
GFP-C57BL/6 hippocampal CA1 NSC ↑neuronal regeneration ・Origin of newly synthesized △ [44]
mice neuron
・mechanism of neural
regeneration
GFP tg mice hippocampus subiculum NSCs delivered NEP ↑synaptic density ・Link between Aβ level and 〇 [45]
↓Aβ cognitive deficit
Key: 〇 changes, △ not mentioned, × unchanged

Neurotrophin release and neurogenesis in 3xTg mice studies, thus partially satisfying the requirements of a
is highly dependent on the source of NSCs. Specifically, typical AD mouse model [6, 48, 49].
in Ager’s study, hNSCs differentiated into immature Lilja et al. transplanted hNSCs into Tg2576 mice treated
neurons and glial cells and induced endogenous synap- with phenserine, which inhibits acetylcholinesterase and
togenesis. Growth-associated protein 43 (GAP-43) is lo- Aβ production by lowering expression of APP, an α7 nico-
cated in the axon to support synapsis and neurite tinic receptor (nAChR) agonist, and JN403. In doing so,
stretching. Interestingly, Ager found that following they could investigate the combined effect of NSCs and
transplantation, GAP-43 was not elevated in the 3xTg drug therapy and found that NSC transplantation was suf-
model [43], thus it is not yet clear how trophic factors ficient to trigger endogenous neurogenesis. In the trans-
from hNSCs affect synaptogenesis in the 3xTg model. In plant region, many α7 nAChR-expressing astrocytes were
contrast BDNF, a member of the neurotrophin family of found, suggesting that such astrocytes are involved in
growth factors, from mNSCs could be involved in the re- repairing damaged neurons and growth of new ones. Des-
covery of synaptic connectivity [23, 45]. The specificity pite combined treatment using both drugs and NSCs, posi-
in NSC differentiation to mature cells and hence the tive effects such as neurogenesis and cognition recovery
subsequent effect of that has been contradicting. Studies was not sustained [50] (Table 2).
involving hNSCs suggest that lineage-specific differenti- In the same animal model, following mNSC transplant-
ation has little effect on cognitive improvement [43], ation at an early stage (13-month-old), changes in both
whereas those involving mNSCs suggest that cognitive pro- and anti-inflammatory cytokine levels significantly
improvement depends on the precise differentiation of influenced Aβ production and clearance rate by altering
the stem cells to allow cell replacement [44]. Moreover, enzyme expression in microglial cells. Furthermore, NSCs
the potential role of stem cells as vehicles for secreting triggered increases in VEGF, endogenous neurogenesis,
degrading enzymes has yet to be thoroughly examined and synaptic density, leading to improvements in behav-
in hNSCs. Although improved behavioural performance ioural performance. However, the same result was not ob-
and cellular changes are observed following transplant- tained after late-stage (15-month-old) transplantation [51]
ation of both hNSCs and mNSCs, the secretory effect (Table 2), suggesting that timely intervention is important.
and role of hNSCs remains poorly understood (Table 1). As described above, both hNSCs and mNSCs can initiate
endogenous neurogenesis. Notably mNSCs alter microglia
Human-derived vs. mouse-derived NSCs in Tg2576 from a pro-inflammatory state to an anti-inflammatory
Unlike the 3xTg model, Tg2576 mice only overexpress state, leading to a decrease in Aβ level through an increase
human Swedish APP (isoform 695; KM670/671NL). in NEP and phosphorylated tau levels. These effects have
These mutations lead to a dramatic increase in Aβ pro- yet to be shown in hNSC studies [50, 51] (Table 2).
duction at about 6 months of age and consequent plaque
formation at 9–12 months. Behavioural impairment is Human-derived vs. mouse-derived NSCs in APP/PS1 mice
observed at 9 months, but some studies have suggested APP/PS1 mice are one of the most commonly used AD
that the mice have no significant behavioural deficit [47]. mouse models. The human APP gene with both Swedish
Mice show no neurofibrillary tangles or significant neur- mutation and PSEN1 (L166P) mutation is incorporated
onal loss, but they display progressive pathological pro- into this model. This inserted human gene produces
tein accumulation and behavioural impairment in many more Aβ than murine APP. Both Aβ 42 and Aβ 40 levels
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 5 of 11

Table 2 Summary of factors and effects after neural stem cell transplantation in Tg2576
NSC Region Factor Effect Not-shown Aβ/tau Ref
Tg 2576 mice
hNSCs Hippocampal DG ↑α7 nAChR-expressing ↑Endogenous ・level of Neurotrophic factor × [50]
astrocytes neurogenesis ・Synaptic density
Feral cerebral cortex of Hippocampal DG ↓β-secretase ↓Aβ production ・The link between microglia and NSC 〇 [51]
pregnant C57BL/6 mice ↑Neprilysin ↓phosphorylated-tau ・level of BDNF
↑Aβ clearance
↓ pro-inflammatory
cytokine
↓inflammatory
microglial activation
↑anti-inflammatory
cytokines,
↑endogenous
neurogenesis ↑synapse
formation
Key: 〇 changes, △ not mentioned, × unchanged

increase with age, yet the ratio of AB42/40 decreases neurotransmitter related to cell viability and synaptic
after plaque formation. Aβ aggregates in the neocortex plasticity [53]. In 2018, a study by McGinley suggested
at the age of 6 weeks and in the hippocampus at about that transplanted hNSCs regulate microglial activation
3–4 months [5, 52]. and thus reduces Aβ levels. Furthermore, the beneficial
Li et al. transplanted hNSCs into this model and found effect of the treatment on behaviour lasted for 4 months
that the treatment promoted synaptic formation without after transplantation [54] (Table 3).
altering Aβ levels. Some introduced hNSCs differenti- In another study, mNSCs transplanted into APP/PS1
ated into neural cells in the central nervous system. In- mice led to a variety of effects, including an increase in
deed, hNSC transplantation enhances neural metabolic synaptophysin and GAP-43, which were in turn associ-
activity by increasing both N-acetylaspartate, as seen ated with an improvement in behaviour accompanied by
after medical treatment, and glutamate, a major synaptic formation [56]. In another study, mNSC

Table 3 Summary of factors and effects after neural stem cell transplantation in APP/PS1 Tg mice
NSC Region Factor Effect Not-shown Aβ/tau Ref
APP/PS1 tg mice
hNSCs Hippocampus hNSCs N- ↑synaptic density ・Level of neurotrophic factor × [55]
acetylaspartate, ↑Neuronal metabolism ・inflammatory cytokine
Glu
hNSCs Fimbria fornix hNSC ↑microglia activation ・Roles of neurotrophic factor in 〇(AB42 [54]
microglial ↓Aβ long-term effects. only)
activation No change in synaptic density ・Anti-inflammatory cytokine
No change in Choline ・Factors affects NSC lifespan
acetytransferase
Non-Tg B6C3 mouse Hippocampus Synapses increase NSC proliferation ・Factor contributes to △ [56]
embryos ↑ synaptophysin and growth synaptogenesis.
factor ・synapse function.
Non-Tg B6C3 mouse Hippocampus NSC ↑mitochondria ↑mitochondrial- ・Synapsis density △ [57]
embryos related protein ・Level of neurotrophic factor
↓mitochondrial fusion factor
optic mitofusion 1&2.
Non-Tg B6C3 mouse Hippocampus NSC ↓GFAP, Iba-1, TLR4 and TLR4 etc. ・Synaptic density × [58]
embryos ↓proinflammatory mediators ・Neurotrophic level
GFP Tg C57BL/6 mice Hippocampus CNL from NSC ↑ChAT mRNA, ・Inflammatory factors × [59]
fetal forebrain ↑ChAT activity
↑ACh concentration
non-Tg B6C3 mouse Hippocampus NSC ↑long-term potentiation ・Inflammatory factors × [60]
↑neuron expressing protein
↑synaptogenesis
↑ BNDF
Key: 〇 changes, △ not mentioned, × unchanged
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 6 of 11

administration induced BDNF and tropomyosin receptor to 6-month ages and continues to worsen [62]. These
kinase B (TrkB) release. Furthermore, introduced mice lack the primary constituent cells of adaptive im-
mNSCs differentiated into neurons to compensate for munity namely T cells, B cells and natural killer cells. This
damaged endogenous neurons. In mNSC-derived neu- facilitates longer persistence of transplanted NSCs, which
rons, TrkB was highly expressed and enhanced the effect will allow long-term efficacy and safety to be evaluated.
of BDNF upon damaged regions. A protein related to When a clinical grade hCNS-SC line was transplanted
memory and learning function—the NMDA receptor 2B into 5xfAD mice, successful engraftment had been ob-
subunit—is also highly expressed after transplantation, served up to five months after transplantation. However,
leading to cognitive improvement [60]. In addition these transplanted hNSC failed to differentiate into neur-
mNSC-derived cholinergic-like neurons, crucial players onal cells and had impact on synaptic density. Pathological
in neurotransmition, were also transplanted into the protein levels Aβ and BDNF remain unchanged and be-
same Tg mice model. As a result, cholinergic acetyl havior impairment was not mitigated [63]. In 2019, Zhang
transferase (ChAT) mRNA and protein were upregu- et al. transplanted iNPCs reprogrammed from human
lated, with an increase in ChAT activity and concentra- mononuclear cells into RAG-5xfAD. In this instance,
tion as well as increased functional synapse density. This rapid differentiation into neurons and astrocytes were ob-
result has further inspired efforts to develop NSC treat- served. Furthermore, these differentiated neurons formed
ments since it addresses both molecular and cellular as- functional interaction with the host neuron, which rebuilt
pects of AD [59]. Zhang et al. investigated alterations in synapses. An increase in BDNF levels was also observed in
inflammatory activity after mNSC transplantation and the hippocampus. Furthermore, behavior improvement
found that the activity of glial cells and astrocytes was was observed at around 5 to 6 moth post-transplantation
decreased after mNSC transplantation. This affected the [64]. It is worth noting that the source of NSCs from these
Toll-like receptor 4 signalling pathway and reduced the two studies are very different, where it is plausible to think
neuroinflammatory response via a cascade reaction. Cog- that reprogrammed somatic cells will have greater neural
nitive improvement was also observed in the study [58]. differentiation capacity. This appears to be the biggest dif-
Although few of these studies tackled the issue of Aβ ference between the two studies, thus suggesting that
levels, they still achieved improvements in behavioural lineage specific differentiation into the desired cell type
performance via synapsis attenuation (Table 3). will have significant effects upon the desired outcome
Some partially contradicting results have been obtained. (Table 4). It is known that the adaptive immune system
In one study, hNSCs rescued cognitive deficits without al- and T cells in particular have a significant role in propa-
tering synaptic density [54], while in another, hNSCs im- gating the neuroinflammatory response [65]. As such, al-
proved synaptic density and neural metabolic activity, but though long-term engraftment of transplanted NSCs was
mitigated behavioural improvement [53]. In some studies, observed, like other mouse models, the accuracy of 5xfAD
hNSC transplantation activated microglia and decreased in modeling AD is also questionable.
Aβ level [54], while a review of mNSC studies found no
change in Aβ levels, although cognitive deficits were res- Mechanisms of behavioral improvement with different
cued. The decrease in pro-inflammatory factors [58], NSC sources
neuron replacement, increase in cognitive related protein Role of hNSCs in Tg models
[60] and rise in effective neuronal transmitter levels [59] Across the 3xTg, Tg2576, and APP/PS1 Tg mouse models,
contributed to this outcome. In contrast, no studies into similar behavioural and cellular effects are produced after
hNSCs have yet directly investigated the role of neuro- hNSC transplantation. In 2015, Ager et al. transplanted
trophic factors, so mNSCs have been more thoroughly in- hCNS-SCs into the 3xTg model and found that the cells
vestigated than hNSCs, even though both hNSCs and differentiate into immature oligodendrocytes, immature
mNSCs yield similar results at the behavioural level. Al- neurons, and a few astrocytes. Their study suggested that
though the precise mechanisms remain controversial, NSCs from hCNS-SC trigger endogenous synaptogenesis,
some form of beneficial effect remains consistent through- leading to cognitive improvement. Additionally, they pro-
out (Table 3). posed that specific differentiation stage has little relevance
in the improvements seen. Instead, they claimed that the
Human-derived NSCs in immune-deficient mice intrinsic properties of hCNS-SCs play an irreplaceable role
5xfAD mice carries a total of five mutation namely, hu- [43]. Similar behavioural improvement is achieved after en-
man APP- the Swedish (K670 N/M671 L), Florida (I716V), dogenous neurogenesis, which is enhanced after hNSC
London (V717I), PSEN1, M146 L and L286 V mutations. transplantation in Tg2576 mice [50]. Likewise, in APP/PS1
Amyloid-beta aggregation begins to occur at 6 weeks of Tg mice, synaptic density and cognitive impairment were
age and extracellular amyloid deposition starts at 8-weeks significantly improved, and neural metabolism was also
age [61]. Spatial and memory impairment is observed in 3 ameliorated, suggesting that NSCs may alter neuronal
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 7 of 11

Table 4 Summary of factors and effects after neural stem cell transplantation in 5xfAD (long-term/about 5 month)
NSC Region Factor Effect Not-shown Aβ/tau Ref
5xfAD mice (Long-term/about 5 month)
hCNS-SCs Hippocampus hCNS-SCs No change in synaptic density ・Inflammatory factors × [63]
No differentiated neuron ・Neurogenesis
No change BDNF
No behavior improvement
iNPCs Hippocampal DG hCNS-SCs ↑synaptic density ・Inflammatory factors 〇 [64]
↑ Neuron ・Effect of respective cell type after neural cell restore.
↑ BNDF ・Neurogenesis
Behavior improvement
Key: 〇 changes, △ not mentioned, × unchanged

metabolic activity [53]. This was not mentioned in the studies, either neurogenesis or synaptic density is
3xTg and Tg2576 models. Conversely, another study enough to rescue part of the cognitive deficit. Aβ ap-
showed that NSC transplantation has no effect on synaptic pears to play little role in behaviour, and both Tg2576
density, but that it does improve behaviour [54]. An oppos- and APP/PS1 mice appear sensitive to NSC-mediated
ite long-term result in transplanting hNSC into RAG- neuroinflammatory changes (Table 5).
5xfAD were obtain from two studies. Nonetheless both
studies show NSCs have successfully engrafted into the host AD iPSCs model
for at least 5 months. Zhang’s study suggests NSCs differen- Cells with self-renewal and multi-potency characteristics
tiation triggers beneficial effect including increase in synap- are ideal platforms for drug screening. For instance, iPSCs
tic density, neural cell number, behavior improvement [64] are associated with fewer ethical concerns and AD-iPSCs
whereas Marsh’s fail to terminally differentiate NSCs [63]. models have successfully recapitualted pathological condi-
This information has complicates the causal link and mech- tion for use in novel drug screening such as the combin-
anism between NSCs and behavioural improvement, which ation of bromocriptine, cromolyn, and topiramate as an
are nonetheless closely correlated. Interestingly, many stud- anti-Aβ cocktail [66], -secretase and β-secretase inhibi-
ies across different models have implied that NSC trans- tors [67, 68]. These drugs inhibit Aβ production and so
plantation does not alter Aβ levels, while only the study on toxic Aβ level decreases. Especially in anti-Aβ cocktail
the APP/PS1 model mentioned microglia-mediated neuro- treatment, toxic Aβ level decrease by more than 60% and
inflammation (Table 5). which has same result as in inhibitors treatment [66].
Moreover, although FAD and sporadic AD neuron carry
Role of mNSCs in Tg models different mutations, decrease in Aβ levels was observed in
Generally, mNSC transplantation rescues synaptic dens- both [67, 68]. Treatment of anti-Aβ antibodies to iPSC-
ity, leading to behavioural improvement in learning and derived neurons have indicated Aβ as upstream of tau
cognition. Together with the 3xTg and Tg2576 mice, hyperphosphorylation. This result further supports known
mNSC transplantation in APP/PS1 mice triggers synap- mechanisms and provides clues in drug development [68].
tic formation. However, in APP/PS1 mice, neurogenesis Although behavioural tests cannot be carried out in cell
has not been investigated. In both Tg2576 and APP/PS1 models, iPSCs model could offer significant contribution in
mice, inflammatory level is altered after the transplant- elucidation of pathophysiological mechanisms as well as
ation. Notably, NEP produced from microglia in Tg2576 drug screening.
decreases Aβ levels [51], while NSC transplantation in
APP/PS1 lowers microglial levels [58]. Neurotrophic fac- Challenges surrounding NSC transplantation
tors such as BDNF are elevated in 3xTg mice and APP/ Although the potential of NSC therapy is promising, the
PS1 Tg mice, but not in Tg2576 mice. Based on these process of developing it as a treatment for AD is similar to

Table 5 Mechanisms of behavioral improvement after neural stem cell transplantation

hNSC mNSC
Synaptogenesis Neurogenesis Inflammation Synaptogenesis Neurogenesis Inflammation
3xTg ○ △ △ ○ ○ △
Tg2576 △ ○ △ ○ ○ ○
APP/PS1 ○ △ ○ ○ △ ○
RAG-5xfAD* ○/× ○/× △ △ △ △
Long-term study Key: 〇, changes; △, not mentioned; ×, unchanged
*
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 8 of 11

any other drugs. To begin with, it is necessary to clearly es- exact mechanism of how NSCs develops into cancerous
tablish the positive impact that it could have on patients. cells remains to be elucidated [72].
However, considering the shortcomings of various AD Ethical concerns around the sourcing of embryonic stem
models, it remains unclear how given outcomes will trans- cells, which can be differentiated into NSCs, have continued
late into human patients. Furthermore, although beneficial, to persist. However, direct isolation of NSCs from primary
the contrasting effect of NSC in different transplantation tissue is extremely risky, and non-patient-specific NSCs
settings further obscures the definite role of NSCs in ther- may cause immune rejection. Using iPSCs as an alternative
apy. Thus, a comprehensive evaluation of NSC transplant- avoids many of the ethical concerns associated with embry-
ation into AD models will be required. onic stem cells. Nonetheless, to what extend these iPSCs
Many studies have associated cognitive improvement are uniformed in their quality remain in question. More-
with increases in synaptic density, which is closely re- over, during iPSCs establishment, reprogramming efficiency
lated to increases in both neuron and glial cell number. is depended on donor-cell-type and reprogramming
NSC transplantation supports both behavioral and cog- method [73, 74]. The optimum somatic cell type for repro-
nitive improvement. However, the exact attributing cell gramming into iPSCs and subsequent differentiation into
type that supports these improvements that NSCs will NSCs remains to be determined. Nonetheless, iPSC-derived
need to differentiate into remains unclear. Although NSCs represents a more readily available source of trans-
NSC transplantation rescues synaptic damage and is in- plantable cells that can be further modified to enhance the
volved in functional interaction with the endogenous beneficial effect of transplantation.
neuronal circuit, few studies have addressed the duration To conclude, the beneficial effect of NSCs is based less
of this effect. It remains to be seen to what extent an im- on modulating pathological protein levels but rather, in-
provement in synaptic density is only a “one-hit” effect creasing synaptic density, restoring local neuron popula-
or something that is more prolonged in the fight against tions, and/or increasing neurotrophic factor levels
disease progression towards a cure for AD. (Fig. 2). The question is how long can this phenomenon
Aβ levels are closely related to the activity of glial cells, persist for whilst levels of pathological protein level re-
which are in turn related to the extent of the inflammatory main unchanged. Also, it would be interesting to know
response. In many studies, various neurotrophins and cy- what role NSC can play in lesion protein aggregation
tokines act as inducers to promote cell protection or the through mediating glial cell, inflammation, and synapse
production of Aβ-degrading enzymes. In fact, NSCs could rescue. All in all, although certain challenges remain,
be genetically modified to highly express Aβ-degrading NSCs will likely have an important role in advancing
enzyme and to proliferate widely. Ideally, continuous pro- treatment for AD.
duction of neurotrophic and degrading enzymes by NSCs
would prevent further neurodegeneration as disease pro-
gresses. However, in practice, Aβ clearance may have little Recent clinical developments in treatment of Alzheimer’s
effect on global improvement, because the basal environ- disease
ment remains favorable for Aβ production and aggrega- Aβ related toxicity is still believed to be the main cause of
tion. Thus, to augment the effects of NSC, the basal synaptic dysfunction and the subsequent neurodegenera-
environment should first be manipulated by influencing tion that underlies the occurrence and development of AD.
local glial cell activity, followed by evaluating transplanted Aducanumab is a monoclonal antibody targeting ag-
NSCs in terms of clearance and production rates, inflam- gregation of Aβ. When transplanted intoTg2576 mice,
mation level, and neurogenesis. dose-dependent reduction in both soluble and insoluble
Localization within the transplant area and viability of Aβ could be occurred and similar observations in a
transplanted cells are the preliminary challenges in NSC phase 1b randomized trial [75]. To follow up, two identi-
treatment. Subsequent interactions with cells in the host cal phase III trials (ENGAGE and EMERGE) were initi-
environment is also important. In some studies, NSCs are ated but unfortunately both were discontinued in March
untraceable after transplantation, while studies with trace- 2019 after failing futility testing. Data was re-analyzed to
able NSCs have not quantified the viable cell number. include those who had completed the 18-month follow-
Methodological difficulties have limited the understanding up between the futility analysis and halting both studies
of NSCs in vivo [69, 70]. The problem of untraceable [76]. In a surprise announcement in October 2019, a
NSCs in studies post-transplantation has yet to be fully new filing for approval for Aducanumab will be made to
studied. Indeed, there is the inherent risk of transplanted the FDA. However, experts in the field are being prudent
NSCs developing into brain tumor such as glioblastomas. over interpretation of the results as only one of the trials
Many studies have identified that cancer stem cells share showed moderate benefit in cognitive improvement
many common features and niches with NSCs and impli- whereas the other trial still showed no hint of efficacy
cate NSCs as the origin these cells [71]. However, the [77]. Similar observation was observed in phase III
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 9 of 11

Fig. 2 Routes for neural stem cell transplantation and mechanisms of cognitive impairment restoration. Transplantation of neural stem cells
triggers (1) endogenous synaptogenesis and (2) endogenous neurogenesis to influence behavioral performance. (3) The limited causal
relationship between amyloid-beta and neural stem cells contraindicates any link between behavioral performance and amyloid-beta aggregation

trials for Solanezumab, which is also targets Aβ ag- bring some positive effects albeit the mechanisms remains
gregation [78]. unclear. The number of variable factors remains high in
Recently in China, conditional approval has been each mouse model, but they fail to compensate for one
granted for Oligomannate, which aims to prevent neuro- another. By comparing hNSCs and mNSCs, only a few
inflammation that can occur through stimulated differen- studies have suggested that Aβ levels in these animal
tiation and proliferation of T helper 1 (Th1) cell by gut models decrease after hNSC transplantation. Thus, know-
dysbiosis [79]. When administered to patients with mild ing the primary cause of AD is highly due to Aβ aggrega-
to moderate AD in a phase III study, significant cognitive tion, the functional and characteristic differences in the
improvement could be observed compared to the placebo two types of NSC must be re-examined. Additionally,
group. However, at the time of writing this review, data temporary recovery of behaviour is relatively easily ob-
for the study has yet to be published. For now, gut dysbio- tained, but often fail to linked to a complete cure. Curative
sis and neuroinflammation remains unproven as an effect- treatment is likely dependent upon sufficiently early diag-
ive in in combating AD progression. Many unanswered nosis to prevent further cell death and brain deterioration.
questions remain for those suffering from more severe A combination of NSC transplantation alongside adminis-
forms of AD beyond moderate levels. Cognitive improve- trating existing approved medication and preventing fur-
ment remains the gold standard by which the efficacy of ther Aβ aggregation may way be the most effective. It
various targeted therapies is judged by. Yet it appears tar- important to note that whilst behavioral or cognitive im-
geting only a single element of AD pathophysiology, such provement is interpreted as positive outcomes, it can be
as Aβ accumulation or neuroinflammation will not be frequently misinterpreted as permanent arrest or even re-
enough to arrest disease progression. versal of AD progression. It merely provides some clues to
future treatment thus the focus should shift towards how
Conclusion and future aspects to sustain such phenomena and combine different treat-
Various animal models have been established and each ment that may give rise to such outcomes.
has its own advantages. None have successfully replicated
Abbreviations
the complex microenvironment of the human brain or the 3xTg: Triple-transgenic; AD: Alzheimer’s disease; APP: Amyloid precursor
precise pathophysiological conditions of AD. Conse- protein; Aβ: Amyloid-beta; BDNF: Brain-derived neurotrophic factor;
quently, it is challenging to precisely characterize the ChAT: Cholinergic acetyl transferase; ESCs: Embryonic stem cells;
FAD: Familial Alzheim’s disease; FDA: Food and Drug Administration; GAP-
beneficial effects of NSCs in AD. However, it has been 43: Growth-associated protein 43; hCNS-SCs: Human central nervous system
consistently shown that transplantation of NSCs does stem cells; hNSCs: Human-derived neural stem cells; iNPCs: Induced neural
Hayashi et al. Journal of Biomedical Science (2020) 27:29 Page 10 of 11

progenitor cells; iPSCs: Induced pluripotent stem cells; mNSCs: Murine- 10. Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist
derived neural stem cells; nAChR: Nicotinic acetylcholine receptor; that improves memory by restoration of homeostasis in the glutamatergic
NEP: Neprilysin; NMDA: N-methyl-d-aspartate; NSCs: Neural stem cells; system--too little activation is bad, too much is even worse.
PS1: Presenilin-1; SVZ: Subventricular zone; TrkB: Tropomyosin receptor kinase Neuropharmacology. 2007;53(6):699–723.
B 11. Atri A, et al. Cumulative, additive benefits of memantine-donepezil
combination over component monotherapies in moderate to severe
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Bioscience and Biotechnology, National Cheng Kung University, Tainan, cognition via BDNF in a transgenic model of Alzheimer disease. PNAS. 2009;
Taiwan. 3Division of Stem Cell Processing/Stem Cell Bank, Center for Stem 106(32):13594–9.
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