Human Induced Pluripotent Stem (hiPS) cell transplantation therapy for a degenerative
eye disease has been reported . Thereafter, the treatment has become to receive much
attention for its potential to rescue the impaired cellular functions of various neurological
disorders, including cognitive dysfunctions in patients with Alzheimer’s disease (AD).
We previously transplanted hiPS cell-derived neuronal cells into the hippocampus in AD
model mice [2,3]. The cell transplantation significantly improved cognitive dysfunction in
the mice. The transplanted neurons differentiated into cholinergic and GABAergic neurons
predominantly in the cerebral cortex and hippocampus, respectively. The characteristic
human neuron distribution in the mouse brain may be partly due to the microenvironments
of the AD lesions, including secretion of chemokines and growth factors, leading to neuronal
It is well known that cholinergic neurons which secrete acetylcholine (ACh) play
important roles in learning and memory functions. The activity of cholinergic neurons and
their Ach production are down-regulated in patients with AD [4,5], and down-modulation
of alpha7 nicotinic ACh receptor (alpha7 nAChR) has been reported as one of the hallmarks
of AD .
On the contrary, previous studies of GABA expression in AD were inconsistent. Several
researchers have reported that the hippocampal GABAergic system was resistant to the AD
pathology to some extent .
We here focus on neurotransmitter secreting neurons derived from hiPS cells and
respective receptor-expressing neurons in the hippocampus of grafted AD model mice. It is
possible that the neurotransmitters secreted by the grafts are involved in the functional and
morphological improvements of mice after the transplantation.
Ach and GABA in the AD hippocampal formation
Basal forebrain cholinergic cells provide the cholinergic projections to the cerebral
cortex and hippocampus. Progress has been made in research into the neuropathology of cells and nucleus basalis of Mynert in patients with AD. The cell
complex is suggested to be divided into four groups, termed Ch1-Ch4,
based on anatomical features, such as nucleus size, neural density,
acetylcholinesterase immunoreactivity, and the innervation area .
Ch1/Ch2 (medial septal nucleus/vertical limb of the diagonal band
nucleus) projects to the hippocampus, whereas Ch3 (horizontal limb
of the diagonal band nucleus) projects to olfactory bulb.
The Ch4 group is the largest out of the four cholinergic neuron
groups and corresponds well with large parts of nucleus basalis
of Mynert. The most AD affected region was the posterior part of
Ch4 group, and the innervated superior temporal and temporal
polar neural loss correlated well with memory loss and language
impairment of AD [8,9]. In contrast, AD neurons of Ch1/Ch2, where
the projection lead to the hippocampus, exhibited only modest
degeneration compared with age-matched control individuals
The Ch1/Ch2 complex, which mainly innervates the CA2/CA3
regions of the hippocampus , plays an important role in learning
and memory . Alpha7 nAChRs are expressed densely in GABAergic
hippocampal interneurons , whose signals are modulated by
cholinergic axons . The most distinctive AD associated neural loss
was observed in the CA1 region of the hippocampus .
One of the major pathological features of AD is the substantial
reduction of cortical cholinergic markers, such as ChAT and
acetylcholinesterase . Distinct nAChR subunit loss in the cortex
and hippocampus was also reported to be related to AD pathology .
The findings of AD-related alterations in GABAergic
neurotransmission are inconsistent in both humans and animal
models . In the early stages of AD, the hippocampal GABAergic
system was suggested to be relatively resistant to AD pathology
compared with glutamatergic neurons .
It was recently reported that down-regulation of Glutamic Acid
Decarboxylase (GAD)67, an enzyme that synthesizes GABA, was more
severe than previously thought in AD patients [20,7]. Researchers
found that distinct parts of GABAR subunits reduced in their
expression in the AD hippocampus . Additionally, postmortem
studies suggested that GABAAR expression was decreased in cortical
areas of AD patients [21,22]. Loss of functional GABAARs in the AD
brain was also observed .
These data suggest that both cholinergic and GABAergic systems
are substantially affected, at least in the later stages of AD.
Neuron transplantation in AD models
Researchers have transplanted various stem/progenitor
cells, such as mouse [24-31] and human [32-36] neural stem/
progenitor cells, mouse [37-41] and human [42,43] mesenchymal
stem/progenitor cells, Embryonic Stem (ES) cell-derived neural
cells [44,45], iPS cell-derived neuronal [2,3,44] and myeloid 
cells, and umbilical cord stem cells  into AD models. The cell
transplantations significantly improved cognitive functions.
In histopathological analyses, the transplanted cells promoted
the formation of synapses [24-27,29,33-35] and decreased amyloidbeta
The cells were transplanted into the hippocampus and/or
ventricle(s) of model mice mainly with the use of needle puncture.
The grafted neural cells showed wide variation in their distribution,
probably due to differences in the characteristics of the grafts, the
transplantation procedures, and the observation periods. When the
grafts were injected into ventricles, grafted cells were distributed
widely around the ventricles  and whole brain [32,37],
approximately 1 - 2 months after the transplantation.
In other experiments, cells transplanted into the hippocampus
remained in close proximity to the grafted sites for 2 – 9 months [29,36,44] and cell numbers gradually decreased [29,36,43].
The transplanted neural stem/progenitor cells tended to migrate
further than mesenchymal stem cells, from
the hippocampus to the cortex [24-26,33,3,31]. After the migration,
the neural cells differentiated into mature neurons,[2,3,25,26,31-34]
astrocytes,[24-26,33,34,31] and oligodendrocytes [24,34,31].
Generation of basal forebrain cholinergic neural cells from
human ES cells has been reported . Yue et al. transplanted these
neurons into the basal forebrain of AD model mice, and cognitive
dysfunction was significantly improved. The neural progenitor
cells migrated along cholinergic projection track from the nucleus
basalis of Mynert towards the cortex and hippocampus. The synaptic
formation between host neurons and grafted cells suggested that
ES cell-derived neurons were successfully incorporated into the
endogenous cholinergic projection system.
Of note is that the grafted mouse neural stem cells differentiated
into cholinergic neurons and exhibited similar positive effects
on ACh concentrations in the brain and cognitive functions in
AD model mice . ChAT overexpressing neural stem cells 
significantly shortened the escape latency of the Morris water maze
test after transplantation, suggesting that oversupply of cholinergic
neurotransmitters improved cognitive function of AD models.
Collectively, the transplantation into basal forebrain restored the
cholinergic projection system and cognitive function in AD rodent
Functional study of learning capability and histological analyses of mice grafted with hiPS cell-derived neuronal stem/progenitors
PDAPP transgenic mice, which overexpress mutated human APP
(APPV717F) , display progressive synaptic loss , reduction
in the size of the hippocampus, and spatial memory dysfunction
starting from a few months of age [50,51]. Furthermore, PDAPP mice
have been shown to have reduced levels of hippocampal Ach .
Mice were left on the platform for 30 seconds before the next
trial was started. For all tested mice, we calculated the average value
of the latency from the four trials performed on each trial day, and we
showed this value as the mean escape latency.
We found that neural cell transplantation improved cognitive
functions (as shorter mean escape latency) of dementia mice (Figure 1A,1B) depicted tracing of the mouse swimming path. Indeed, total
swimming time until reaching to the platform of the grafted mice was
Figure 1:Transplantation of the neural stem/progenitor cells restored spatial memory learning in dementia model mice.
A. Hidden test was conducted for 4 consecutive days after visible test. Twenty-two days after neural cell transplantation, the grafted mouse showed shortening of mean platform escape latency. The improvement has become more evident 45 days after the transplantation.
B. Tracing of the swimming path of a representative mouse after neural stem/progenitor cell transplantation. The mouse swimming path
was captured by CCD camera and analyzed. Total swimming time until reaching to the target platform of the grafted mice was clearly
shortened after 22 days. The improvement has become more evident 45 days after the transplantation.
Video of Figure 1:
(A) Video of the trajectory of the TG mouse in the third picture from the left in the first row of Fig. 1B. It was made before transplantation in the third trial of the first day of the hidden test. The mouse was unsuccessful to reach the platform located on the near left side.
(B) Video of the the trajectory of the same TG mouse in the third picture from the left in the second row of Fig. 1B. It was made 22 days after transplantation in the third trial of the first day of the hidden test. The mouse was successful.
Histological analysis disclosed that ChAT+ neurons distributed
throughout the overlying cerebral cortex around the injection site
(Figure 2)ChAT+ neurons composed a quarter of the nucleated
cells, of which half were human neurons, and the remaining half
were mouse neurons. In the cortex of the grafted mice, half of the
nucleated cells were alpha7 nAChR+ neurons. It was surprising
that the distribution of cholinergic neurons and GABAergic neurons
was clearly and consistently different from each other after the
transplantation. We suggested that cortex-locating grafts may
compensate for the depletion of Ach in the cortex, which was caused
by the basal forebrain Ch4 projection loss .
Figure 2:Distribution of human neurons after transplantation
of hiPS cell-derived neuronal cells in the AD model mice. The
neuronal cells were initially grafted at the hilus of the DG in the
mice. A couple of months later, the grafts migrated and were
distributed as shown below.
A. Immunohistochemical staining of the hippocampus grafted with
hiPS cell-derived neurons. Human cells were detected by antihuman
nuclear protein antibody (hNuc; red). GABA producing
cells were detected by anti-VGAT antibody (green). The cells were
counterstained with DAPI (blue).
B. Distribution of hiPS cell-derived neurons after transplantation.
Human cholinergic neurons (red) located throughout the cortex
and the CA3 and CA1 of hippocampus. GABAergic neurons (green)
located predominantly within the hippocampus, especially near
the interface of the DG and CA3. The distribution of both cell types
was clearly different from each other after the transplantation. A
white rectangle in the cortex indicates the proposed area of the
posterior parietal cortex, which plays a role in spatial navigation
in rodents .
In the hippocampus, ChAT+ neurons were located around the
injection site in the DG. In the hippocampus, one third of the nucleated
cells were alpha7 nAChR+ neurons. A substantial numbers of mouse
ChAT+ neurons and mouse alpha7 nAChR-expressing cells were
observed in the grafted mouse hippocampus. Thus, it was possible
that hiPS cell-derived neurons altered the differentiation of mouse
neural stem/progenitor cells, increasing ChAT+ neurons and alpha7
nAChR expressing cells in the grafted mice. These ChAT+ neurons
emerged after neuronal cell transplantation in both the cortex and
hippocampus, and may contribute to the functional recovery of
PDAPP mice. However, detailed analyses of the grafted mice with
regard to their ChAT+ and receptor expressing neurons, especially
neuronal circuits reconstituted by the grafts, are yet to be performed.
As mentioned previously, AD findings in the human GABAergic
system were inconsistent, but GABAergic interneuron loss was
obvious in several AD models . Impaired GABA functions were
observed in PDAPP mice , tau protein transgenic mice ,
and apolipoprotein (apo) E 4 knock-in/APP mice . These mice
exhibited defective hippocampal functions including GABAergic
neuronal loss and/or dysfunction and memory deficits.
Carrying the epsilon4 allele of the apoE4 gene was a strong risk
factor of AD for humans , and apoE4 directly impaired GABAergic
inhibitory neuron function . GABAergic interneuron progenitors
transplanted into the hippocampal hilus were functionally integrated
into the host hippocampus and improved learning and memory
function in apoE4 knock-in/APP mice . Thus, alteration in the
inhibitory/excitatory balance may underlie the symptomatic changes
in patients with AD .
Several reports supported the concept that reduction of inhibitory
GABAergic synapses was associated with the pathogenesis of AD .
Nonetheless, we have to be careful to understand the importance
of GABA production in patients with AD. Excessive production of
GABA by glial cells may have important roles for the development of
neuro-inflammation, leading to neuronal cell death [61,62]. We, and
others, focused on GABA-producing neurons and GABAR-expressing
neurons. These differences may contribute to differences in the role
of GABA in the pathogenesis of patients with AD.
We observed that the majority of VGAT-expressing cells were
located around the grafted area in the hippocampus, where defective
GABAergic neuronal functions were reported in the dementia model
mice [63-65]. With our transplantation protocol, in order to aid reconnection
with a shorter distance by axons of the graft between
CA1/CA3 and DG of host, we put the cells at the hilus of the DG of
the bilateral hippocampi . Thereafter, we found that VGAT+ and
GABAR+ neurons were distributed in the hippocampus, especially in
the hilus of the DG (Figure 2,3).
Figure 3:Possible mechanisms of GABAergic inhibitory
neuron-induced beneficial effects on neuronal networks of the
hippocampus in dementia model mice.
The grafts were initially put on hilus of the DG.
A. A schematic representation of VGAT/GABAR-expressing host
cells in the hippocampus of normal mice.
B. A schematic representation of VGAT/GABAR-expressing host
cells in the hippocampus of aged PDAPP mice. VGAT+ and
GABAR+ cells decreased in number, especially in CA1 and
C. A schematic representation of host and human VGAT/GABARexpressing
cells in the hippocampus of neuron-transplanted
PDAPP mice. VGAT+ cells extend their axons both to the
pyramidal cell layer (or at least the molecular layer) and
the granule cell layer, to bring about re-connection of their
neuronal pathways [Suzuki et al., unpublished observation].
D. A schematic representation of amyloid-beta protein deposits
in the hippocampus of PDAPP mice. Synaptic spillover
of GABA may act on GABAR-expressing cells and inhibit
protein-mediated apoptotic neuronal cell death.
VGAT expressing cells composed 10% of the nucleated cells in the
hippocampus, and more than 30% of the VGAT positive neurons were
human neurons in the hippocampus of the grafted mice. GABAAR+
neurons composed 2.3% of the nucleated cells in hippocampus. In
the hippocampus, more than 80% of GABAR expressing neurons
were mouse cells.
Taking into account of the fact that the grafts were persistently
located near the hilus of the DG, possible mechanisms of restoration
of hippocampal cognitive functions by neuronal cell transplantation
- VGAT+ cells extend their axons both to the pyramidal cell layer
(or at least molecular layer) and the granule cell layer to bring
about re-connection of their neuronal pathways (Figure 5C) [67,
- Synaptic spillover of GABA may act on GABAR expressing cells and
inhibit protein-mediated apoptotic neuronal cell death (Figure
Indeed, our preliminary experiments suggested the re-connection
by the grafted VGAT positive cells with cells in the granule cell layer
and cells in the pyramidal cell layer occurs either directly or indirectly
. Thus, phasic inhibition of the connection among grafts and
host neurons may play a crucial role in the behavioral improvement
of neuron transplanted PDAPP mice. This hypothesis is consistent with the data of an association between the long-term potential
impairment and increased tonic inhibition of GABA in hippocampal
neurons of AD model mice [62,73-76]. Possible histological
restoration by hiPS cell-derived neuronal cell transplantation into
the PDAPP mouse hippocampus is shown in (Figure 3B,4), where
inhibitory output provided by the hiPS derived GABAergic neurons
may restore the alterations in the inhibitory/excitatory balance.
Figure 4:Possible neuronal re-connection by hiPS-derived neuronal
transplantation (A part of the figure in “The synaptic organization
of the Brain, ED. Gordon M, Shepherd, Oxford University Press
(2003)” is modified).
A. Unique unidirectional progression of excitatory pathways
(arrows) links each region in the hippocampal formation of
B. Several neural pathways are suggested to be preferentially
affected in the hippocampal formation of AD model mice
(dashed lines) . Red lines indicate possible inhibitory
output by the VGAT+ hiPS cell-derived neurons.
EC, Entorhinal Cortex; DG, Dentate Gyrus; CA, CornuAmmoni
We are currently investigating the possibility shown in (Figure 5),
where Gutierrez suggested a possible role of CA3 interneurons in the
granule cell-CA3 pyramidal cell connection .
Figure 5: Possible role of hiPS cell-derived GABAergic neurons
in the grafted dementia model mice. Activation signals mediated
by glutamatergic neurons may be controlled by the hiPS derived
neurons (shown in green), thus, they may substitute for the CA3
interneurons lost in dementia model mice (Parts of the figure in
“Gutierrez, 2016” are modified).
A. The granule cells of the DG excite pyramidal cells, through
giant MF (mossy fiber) boutons. The granule cells excite CA3
interneurons to release GABA, inhibit CA3 pyramidal cells, and
sustain feed-forward inhibition, through boutons en passant
and filopodial extensions.
B. The granule cells of the DG excite pyramidal cells through giant
MF boutons. The granule cells excite the hiPS cell-derived
GABA interneuron to release GABA, inhibit pyramidal cells,
and sustain feed-forward inhibition, through boutons en
passant and filopodial extensions.
C. An inhibitory response in CA3 pyramidal cells after mossy fiber
stimulation due to activation of CA3 interneurons.
D. An inhibitory response in pyramidal cells after mossy fiber
stimulation due to activation of hiPS cell-derived GABA
In panel A, granule cells of the DG excite pyramidal cells, through
giant boutons. The granule cells excite CA3 interneurons to release
GABA, inhibit pyramidal cells, and sustain feed-forward inhibition,
through boutons en passant and filopodial extensions.
In panel C, an inhibitory response in pyramidal cells to mossy
fiber stimulation is due to the activation of interneurons.
We agree with his proposal and taking his proposal into account,
we think that our VGAT+ cells substituted the role of CA3 interneurons
lost possibly by apoptosis in dementia mice (neurons colored in
green in panels B and D). Our preliminary observation suggested that
hiPS derived VGAT+ neurons acted on pyramidal cells located in the
CA1 and CA3 (panels B and/or D).
Thus, it is possible that our neuronal cell transplantation, which
supplemented GABA+/ GABAAR+ cells in the hippocampus, restored
impaired GABA/GABAAR circuits in the hippocampus of the PDAPP
mice, leading to the restoration of their defective cognitive functions.
In support of our findings, the importance of GABA/
GABAAR circuits was also revealed by administrations of GABA/
GABAAR modulators. NMZ, a positive allosteric modulator of
GABAA function, which potentiates the function of the inhibitory
neurotransmitter GABA in the brain , attenuated the glutamateinduced
excitotoxic cascade leading to the inhibition of mitochondrial
damage and neuronal loss [78-80].
Selective pharmacological activation of GABAA receptors has been
shown to provide neuroprotection against amyloid-beta mediated toxicity, likely through the arrangement of the protein cleavage
process . In vitro, chronic activation of GABAA receptor agonists
protected cultured neurons against the neurotoxicity of amyloid-beta
. However, treatment with picrotoxin, a GABAAR antagonist, also
improved the cognitive functions of adult APP/PS1 mice .
These findings suggested that phasic and synaptic signals of
substances with precise recognition of the receptors’ subunits were
important for the improvement of AD memory loss.
However, glial production of GABA, possibly by inflammatory
responses, may have other implications for the AD pathogenesis .
Further studies are needed to clarify this.
Thus, the interaction between GABA, secreted predominantly
by the grafted neurons, and receptor (GABAR) expressing grafted
neurons and host neurons, may underlie the improvement of memory
performance in the PDAPP mice that have undergone transplantation.
Transplantation of hiPS cell-derived neurons is a promising
candidate for the treatment of advanced AD. The graft’s autonomous
effects on the regeneration of damaged neuronal circuits, possibly
involving ACh and GABA are attractive mechanisms for clinical
application. Further studies are needed to confirm the roles of ChATpositive
cells and VGAT-positive cells in functional recovery before
conducting clinical application in patients with AD.
This study was partly supported by Grants-in-Aid for Scientific
Research of Japan Society for the Promotion of Science. The funders
had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
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