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Recent Perspective About the Amyloid Cascade Hypothesis and Stem Cell-Based Therapy in the Treatment of Alzheimer's Disease

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Alzheimer's disease (AD) is a complex neurodegenerative condition that is clinically characterized by impaired cognitive functions. The major morphologically observed lesion of AD encompasses the accumulation of extracellular amyloid aggregates (plaques) formed of amyloid-β (Aβ) protein and of intracellular neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein. According to the currently accepted amyloid cascade hypothesis, the major induction factor underlying the loss of cholinergic neurons in the cortex and hippocampus is the pathological accumulation of a smaller protein fragments known as amyloid-β which in turn is
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FCDR-Alzheimer Disorder, 2016, Vol. 5, 3-33 3
CHAPTER 1
Recent Perspective About the Amyloid Cascade
Hypothesis and Stem Cell-Based Therapy in the
Treatment of Alzheimer's Disease
Hany E. Marei1,*, Asmaa Althani1,2, Jaana Suhonen3, Mohamed E. El
Zowalaty1, Mohammad A. Albanna4, Carlo Cenciarelli5, Tengfei Wang6,
Thomas Caceci7
1 Biomedical Research Center, Qatar University, Doha, 2731, Qatar
2 Department of Health Sciences, College of Arts and Science, Qatar University, Doha, 2731,
Qatar
3 Neurology Department, Al-Ahli Hospital, 6401 Doha, Qatar
4 Psychiatry Department, Hamad Medical Corporation, 3050 Doha, Qatar
5 CNR-Institute of Translational Pharmacology, Via Fosso del Cavaliere, 100-00133 Roma-Italy
6 Department of Pharmacology, University of Tennessee Health Science Center, Memphis,
Tennessee
7 Department of Biomedical Sciences, Virginia-Maryland Regional College of Veterinary
Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
Abstract: Alzheimer's disease (AD) is a complex neurodegenerative condition that is
clinically characterized by impaired cognitive functions. The major morphologically
observed lesion of AD encompasses the accumulation of extracellular amyloid
aggregates (plaques) formed of amyloid-β (Aβ) protein and of intracellular
neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein. According to the
currently accepted amyloid cascade hypothesis, the major induction factor underlying
the loss of cholinergic neurons in the cortex and hippocampus is the pathological
accumulation of a smaller protein fragments known as amyloid-β which in turn is
* Corresponding author: Hany Marei: Biomedical Research Center, Qatar University, P.B. Box 2713,
Doha, Qatar; Tel: (+ 974) 4403-6817; E-mail: hmady@qu.edu.qa
Atta-ur-Rahman (Ed)
All rights reserved-© 2016 Bentham Science Publishers
4 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
derived from a larger membrane protein called amyloid precursor protein (APP). Based
on this hypothesis, several diagnostic and drug-based therapeutic interventions were
suggested, mostly targeting amyloid-β and hyperphosphorylated Tau proteins. Several
data have emerged that might indicate the inconsistency of the amyloid cascade
hypothesis. Moreover, due to the purely palliative nature of AD drugs used so far, new
stem cell-based therapy has been suggested as a promising potential therapeutic
approach. Several cell sources have been used, such as embryonic stem cells, neural
stem cells, mesenchymal stem cells, and induced pluripotent stem cells. While this
suite of cell-based trials has shown promising results in preclinical paradigms,
stumbling blocks still exist in the current treatment regimens. The present review
highlights the recent perspective that argues against the long standing amyloid cascade
hypothesis as well as the major efforts in the experimental application of stem cell-
based therapies used as treatment options for AD, and discusses the major impediments
against their successful translation into clinical.
Keywords: Aβ42 peptides, Alzheimer's disease, Amyloidogenesis, Amyloid beta
protein, Amyloid precursor protein (APP), Neuronal stem cells, Pathogenesis,
Senile, plaques, Stem cells-Therapy.
ALZHEIMER’S DISEASE PATHOPHYSIOLOGY
Since the discovery of Alzheimer’s disease (AD) in 1907, two major pathological
AD associated proteins composed of amyloid β (Aβ), a small fragment of a larger
precursor protein called amyloid precursor protein (APP) and a microtubule-
associated intraneuronal tau protein have been incriminated as the major etiology
underlying the massive loss of cholinergic neurons in the cortex and hippocampus
of the brain [1 - 3]. Using Sephadex G-100 column chromatography, and by high
performance liquid chromatography, a purified protein was derived from fibrils in
cerebrovascular amyloidosis associated with Alzheimer's disease has been
isolated. This protein have no homology with any protein sequenced, and may
provide a diagnostic test for Alzheimer's disease and a means to understand its
pathogenesis [4].
A monoclonal antibody to the microtubule-associated protein tau (tau) labeled
some neurofibrillary tangles and plaque neurites, the two major locations of
paired-helical filaments (PHF), in Alzheimer disease brain. [5].
Massive neuronal loss is associated with major synaptic losses reflected clinically
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 5
as gradual loss of recent memory functions and late-life dementia [6]. Based on
the observed AD-associated pathology, the “amyloid cascade hypothesis,” was
proposed [7, 8]. Major evidence for this hypothesis included the discovery that
mutations of APP genes are among the major genetic makeup of AD [9, 10].
During the last century, the amyloid cascade hypothesis represented the roadmap
by which AD can be diagnosed and treated. Unfortunately, in most cases, this
simple straightforward linear hypothesis failed to explain the complex biological
and molecular pathways associated with the perplexing and devastating AD
pathology. Smith et al. [11] stated that alternate interpretations of old data as well
as new evidence indicates that amyloid-beta, far from being the harbinger of
disease, actually occurs secondary to more fundamental pathological changes and
may even play a protective role in the diseased brain. These findings bring into
doubt the validity of the Amyloid Cascade Hypothesis as the central cause of
Alzheimer disease and, consequently, the potential usefulness of therapeutic
targets against amyloid-beta protein. This became more clear when many of
and tau-protein-based preclinical and clinical trials failed to restore lost neuronal
and cognitive functions associated with AD pathology [12, 13].
The palliative nature of AD drugs developed so far and the failure of amyloid and
tau-based therapeutic protocols have prompted several investigators not only to
point out the possible inconsistency of the amyloid cascade hypothesis, but also to
start searching for novel non-drug based therapeutic protocols such as stem cell-
based therapy [14]. In this respect, several cell sources have been used with the
aim to provide an ample supply of suitable progenitor cells that might restore the
lost neuronal and synaptic elements associated with AD [15, 16].
This review explores novel data that may modify or replace the amyloid cascade
hypothesis, and presents major experimental findings relevant to stem cell-based
therapy for AD.
GENERAL VIEW ABOUT AD
AD represents one of the major public health burdens in elderly population. The
ratio of AD occurence is approximately one to nine in individuals of age < 65 year
old and such figures worsen as the population of the world ages to approximately
6 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
one in three over 85 years age [17]. AD pathology as collected and depicted in
Fig. (1) include massive loss of cholinergic neurons in different brain areas such
as the substantia nigra, subcortical structures such as the basal nucleus of Meynert
and the locus coeruleus are also damaged [18].
Fig. (1). Schematic representation of the pathology of Alzheimer’s disease depicting the multifactorial
perplexed feature of AD disease. The figure depicts the role of amyloid-β (Aβ) in the formation of
extracellular amyloid aggregates which in turn will results in the formation of Tau aggregates and
neurofibrillary tangles (NFTs) which contribute to the neuronal loss, synaptic dysfunction, and diseased
neurons characteristic of AD. In addition, the periplaque activation of astrocytes, resulting in the release of
various cytokines (CK), and microglia, leading to the generation of superoxide radicals (O2-). The
contribution of damaged mitochondria due to aging plays a role in the accumulation of free radicles which
leads to change in the energetic efficiency of neuron. The loss of Ca2+ homeostasis explained by the
excitotoxic activity is a core contributing cause in AD pathogenesis. Changes in the gut microbiome
composition may also contribute to AD pathology. [Parts of the figure were reproduced with permission from
references [17, 27, 32]].
A major hallmark of AD pathology is the deposition of amyloid β and
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 7
hyperphosphorylated tau; this is usually associated with dramatic synaptic loss [2,
19]. These lesions explains the well-known AD symptoms ranging from loss of
memory for recent events to complete dementia with severe behavioral symptoms
such as apathy and depression [20, 21]. It is important to indicate that the
inclusion of such hallmarks is arbitrary and perpetuates the difficulty of properly
studying the etiology of AD, because it is nothing more than a tautological
element in support of the amyloid cascade hypothesis: amyloid must be present in
the brain in order for a patient to be defined as suffering from dementia of the AD
type. That, by definition, eliminates the sub-population of clinically diagnosed
AD patients with no amyloid load from the AD category, and hampers progress
on our understanding of the disease.
GENETIC BASIS OF AD AND AMYLOID CASCADE THEORY
First, it is important to highlight that he pathogenic sequence of familial and
sporadic AD are very different, and that there is no published evidence indicating
that the latter begins with amyloid accumulation. Thus, the genetic basis of AD
only applies to the familial form of the disease. A detailed discussion of this issue
can be found in Ageing Research Reviews [21]. AD is a genetic disease and the
two forms of the disease are recognized as early- and late-onset AD. Mutations in
the amyloid precursor protein (APP) gene interfere with the normal cleavage
process of APP leading to the formation of pathologic proteins especially in early
onset AD [22].
Under normal conditions, the micro processing of APP involves two consecutive
cleavage events [12, 24]. The first cleavage as was shown in Fig. (2a) occurs
close to the outer cellular membrane and is mediated by the extracellular protease
α-secretase leading to the formation of a soluble extracellular fragment sAPPα
[10]. The second cleavage occurs within the membrane by an enzyme known as
γ-secretase and leads to the formation of an intracellular peptide known as
amyloid intracellular domain (AICD) and smaller peptides between the α- and γ-
secretase cuts [10]. The benign nature of the second cut is mediated by one of the
presenilin proteins, encoded by either psen1 or psen2 genes which affect the
catalytic subunit of γ-secretase [10].
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Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 9
Fig. (2). The amyloid cascade hypothesis of Alzheimer’s disease representing the classic theory of the
origination of Alzheimer’s disease (AD). The amyloid protein precursor (APP) is processed by two
consecutive proteolytic pathway events. The first cleavage (a) occurs close to the outer membrane and is
mediated by membrane embedded α-secretase which leads to the release of soluble extracellular domain
(sAPP- α) and smaller peptides between α and γ secretase cuts, which are cleared in normal neurons. In AD
(b), the APP metabolism is shifted from alpha to beta cleavage products by β- and γ-membrane embedded
secretases. leading to the formation of extracellular Aβ monomers and oligomers which contribute to the
formation of the senile plaques or amyloid aggregates, the enzymatic activation of caspases through TERM 2
receptor, formation of neurofibrillary tangles, neurodegeneration, and eventually cell death. Both processes
produce identical intracellular C-terminal fragments (AICD), C-terminal fragment (CTF), and N-terminally
truncated Aβ (p3). Parts of the figure were reproduced with permission from reference [20, 23]. Additional
part of the figure were used with permission from Mayo Foundation for Medical Education and Research,
Rochester, Minnesota, USA.
The α-secretase first cut is defective in case of AD as was shown in Fig. (2b) and
APP is cleaved farther from the membrane by an aspartyl protease enzyme known
as β-secretase, followed once again by γ-secretase cleavage [10]. The amino acid
residue between the two cuts is mediated by β and γ cleavage sites form the
amyloid-β (Aβ) peptide. The Aβ accumulates in the form of oligomers leading to
the formation of amyloid plaques [25, 26].
The main genetic predisposition factor of AD encompasses three main genes APP,
PSEN1, and PSEN2 which are implicated in the early onset, familial AD (fAD)
[10]. Various mutations of these key player genes are known to interfere with
APP cleavage, leading to increased production of Aβ42 which is implicated in AD
pathology [10]. This observation argues in favor of the amyloid cascade theory.
Other supporting evidence for the amyloid cascade theory stems from the recent
observation that mutation of APP near the β-secretase cleavage site interferes with
the function of β-secretase, leading to decrease of Aβ production, and thus
presumably having a protective role against AD pathology [27].
The Amyloid Cascade Hypothesis
The AD pathology develops gradually over a considerable period of time and it is
explained by the imbalance in Aβ production and/or clearance. The amyloid
hypothesis model was first proposed by Glenenr and Wong [28, 29]. The
oligomeric and fibrillar forms of are the main driving factors behind the
development of AD pathology which includes neuronal loss, synaptic dys-
10 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
function, and formation of neurofibrillary tangles [30].
Argument Against the Amyloid Cascade Hypothesis
The amyloid cascade hypothesis was poorly supported as summarized in Fig. (3)
solely on the basis that AD genetics, involvement of APP, and its processing by
presenilin. The amyloid cascade model did not provide a direct enough evidence
for the involvement of Aβ as the main cause behind the initiation of AD pathology
[31 - 33].
Fig. (3). Challenges to accept the amyloid cascade hypothesis. The figure depicts the different
observations, controversies, and anomalies that have important implications in explanation of the
pathogenesis of AD on the sole basis of amyloid β protein concept. [Parts of the figure were used with
permission from Mayo Foundation for Medical Education and Research, Rochester, Minnesota, USA].
Despite the fact that amyloid cascade hupothesis is largely dependent on the
presence of mutations of APP genes, uptill now there hypothesis was no evidence
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 11
that clearly link mutations in APP, and AD symptome. Moreover, no mutations
were reported in either the β- or α-secretase, major enzymes responsible for
cleavage of APP, that either lead to inductions of fAD or guard againist it [33].
Furthermore, the sporadic form of AD (sAD) is more prevalent that fAD, and its
high risk is caused mainly by mutation in the apolipoprotein E (APOE) gene
leading to a two-amino-acid switch in its normal amino acid sequence, thus
producing the APOE4 variant of the protein [31]. Thus, sAD does not appear to
involve genes for either APP or secretases as risk factors which might argues
against the amyloid cascade hypothesis [10, 34].
Results from several experimental and clinical trials argue against the amyloid
cascade hypothesis. In some individuals, massive amounts of amyloid aggregates
could be localized in the brain with few if any clinical AD symptoms; thus
amyloid is not sufficient to cause disease [35, 36]. Transgenic mice that carry a
variant defective human APP gene together with a mutated form of presenilin 1
and 2 produce substantial amounts of amyloid in their brain and despite their poor
performance in tests of spatial memory (such as the Morris water maze) they
never develop any of the well-known AD pathology [37]. Moreover, transgenic
mice that express amyloid-β peptide only, with no APP expression, develop a
considerable amount of amyloid-β with no cognitive deficits [37], such data thus
provide a strong suggestion that Aβ alone is not sufficient to cause the complex
AD symptoms and pathology.
Beside apoE polymorphisms which are being linked to differential AD risks,
current genome-wide association studies (GWAS) expand the early findings on
apoE and highlight three key pathways as being linked to AD risk: cholesterol
dysregulation, immune response and endocytosis. An increasing number of results
implicating cholesterol metabolism in the pathophysiology of ADCholesterol, its
transporter in the brain, apolipoprotein E, amyloid precursor protein, and amyloid-
beta all interact in AD pathogenesis [38].
Removal of macroscopic plaques in mice through active and passive
immunization against the Aβ peptide and the use of anti-inflammatory drugs was
shown to be effective in removing amyloid plaques from the brain [39, 40]. The
12 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
clearance of plaques was associated with improvement in behavioral
performance and restoration of the damaged neural networks. The rapid and
nearly complete restoration of normal behavior may indicate that although these
models may reproduce some of the early stages of AD, they do not fully represent
the massive permanent damage that occurs along the course of AD in human
patients [39, 41].
Immunization against in humans was tested in sAD subjects. Several
participants have developed anti-amyloid antibodies and the plaque pathology was
reported to be drastically reduced [42, 43]. Despite the great reduction in plaque
load, the associated cognitive impairment did not improve, and in most cases the
dementia appeared to be aggravated [44]. The most likely reason for this
phenotype is the proposed protective role of amyloid in the brain. Understanding
such role would clearly provide the intellectual framework that is currently
missing in the discussions on the amyloid cascade hypothesis. In that regard,
amyloid can be protective against upstream pathogenic triggers, such as
cholesterol, inflammation and oxidative stress that are more solidly linked to AD
than amyloid itself, both by GWAS as well as by population studies. This notion
is a significant conceptual contribution to the debate, first proposed by the Perry
lab, and has been discussed at length in the following references [21, 45].
Further arguments against the amyloid cascade hypothesis were deduced from
repeated failure of clinical trials to demonstrate possible beneficial effects of anti-
amyloid-β antibody therapy even after as much as 80 weeks of therapy [46, 47].
Therefore, AD pathology cannot be only explained based on a simple linear
model such as the amyloid cascade hypothesis. Instead, there are alternative
hypothesis to account for the development of the disease [48]. AD is a complex
array of the lesions including damage in the brain’s neuronal circuits, synaptic
failure, neuritic atrophy, tauopathy, failure of autophagy, and lysosomal functions
[49 - 51], and a loss of Ca2+ homeostasis which may be explained by the
excitotoxic activity. These are considered the core mechanisms of AD [52 - 57].
Other studies have suggested that AD is associated with a failure of neuronal cell
cycle control [58 - 67], neuroinflammation [68 - 73], progressive oxidative
damage [74] that accumulates with age [75], DNA damage [76 - 83], loss of
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 13
mitochondrial function [84 - 86], or a complex senescence phenotype [87]. More
recently, the involvement of human microbiota including bacteria and fungi in the
secretion of lipopolysaccharides (LPS) and other related pro-inflammatory and
neurotoxic substances which significantly contribute to AD-related neuro-
degeneration and age-related neuroinflammation [88 - 91]. Other possibilities
include impairment in glucose metabolism [92, 93] or a general metabolic
compromise [94 - 96]. Although Aβ was believed to be the most frequent
underlying cause concomitant of the AD disease process, much evidence suggests
that it is neither necessary nor sufficient alone to induce the AD associated
damage. Each of the aforementioned processes may contribute in important
pathways towards the development and progression of AD disease [31]. Recent
GWAS studies have provided the strongest available evidence that other, non-
amyloid factors are involved in late onset AD. This topic has been discussed at
length in our recent paper [97].
Stem Cell-Based Therapy for AD
It was previously shown that the pathogenesis of AD is probably multifactorial.
Effective therapeutic strategy for the treatment of AD has not yet been available.
AD therapy should be comprehensive and tackle the complex multiple factors
contributing to the pathophysiology pathogenicity of the disease. Recently, stem
cell technologies have succeeded in generating different types of neuronal and
glial cells from different types of stem cells. This achievement may be a crucial
step in providing hope for the possible use of stem cell therapeutics as a novel
treatment for AD [98 - 109].
Neural Stem Cell-Based Therapy for AD
Neural stem cells (NSC) are multipotent progenitor cells located in specific
regions of the brains such as the subventricular zone (SVZ), the subgranular layer
of the hippocampus, and olfactory bulbs. The cell characteristics fit well with the
standards criteria for any viable stem cells, namely: the ability to self-renew, the
ability to differentiate into different kinds of nervous tissue-specific cells
(including neurons, astrocytes, oligodendrocytes) and the ability to replace
damaged tissue following their engraftment as shown in Fig. (4). NSC have been
14 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
isolated from human fetal brain tissue [110, 111] and from different regions of
adult human brain such as the olfactory bulb [112 - 115], cortex, hippocampus,
and SVZ of the lateral ventricles [116]. Isolation of NSC from the human
olfactory bulb (OB) provides a promising approach to cell-based therapy for AD
which overcomes possible immunorejection, avoids ethical issues raised by the
use of human embryos, and provides a chance for personalized medicine [117].
NSC can be transplanted either as a wild type or can be genetically engineered to
overexpress several active substances of known trophic influences for different
elements constituting the CNS tissues [118].
Fig. (4). Schematic representation showing the differentiation of neural stem cells (NSCs) into different
types of nervous tissue-specific cells including neurons, astrocytes, or oligodendrocytes and the ability of
these cells to replace damaged tissue following their engraftment. NSCs may be genetically programmed to
produce neurotrophic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor, and
vascular endothelial growth factor.
The marked ability of NSC to differentiate into neurons, astrocytes, and
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 15
oligodendrocytes following transplantation seems to be promising for cell-based
therapy. In our previous studies, NSC isolated from the adult human OB
(OBNSC) were able to proliferate in culture for several months [118]. The
OBNSC differentiated into MAP2-immunoreactive mature neurons (17.5%) in the
presence of 1% fetal bovine serum, β-tubulin immature neurons (5%), astrocytes
(75%) and fewer oligodendrocytes (2.5%). The human OBNSC were genetically
modified to overexpress human NGF (hNGF) and green fluorescent protein (GFP)
genes [119]. Engraftment of human OBNSC into the hippocampus of an ibotenic
acid-treated AD rat model restored memory deficits and hippocampal histo-
architecture [112 - 115, 118]. Transplantation of F3. NGF human NSCs in mice
following ibotenic acid-induced hippocampal damage was associated with
improved cognitive functions, and restoration of lost neurons within the
hippocampal regions, indicating the positive neurotropic effects exerted by the
biological action of hNGF [120]. Direct intracerebral engraftment of NSC
genetically modified to over-express nerve growth factor (NGF) gene promoted
the hippocampal regeneration and restored age-related atrophy of cholinergic
neurons [121].
Neurotrophins activate a number of signalling pathways relevant to neuro-
protection; however, their poor pharmacological properties and their pleiotropic
effects resulting from interaction with the p75(NTR)-Trk-sortilin three-receptor
signalling system limit therapeutic application [122]. The traditional perspective
of applying neurotrophins in the context of Alzheimer's disease is based on the
premise that neurotrophins are capable of upregulating cholinergic function and of
rendering neurons less vulnerable to certain processes causing degeneration [123].
Neurotrophins have potential for the treatment of neurological diseases. However,
their therapeutic application has been limited owing to their poor plasma stability,
restricted nervous system penetration and, importantly, the pleiotropic actions that
derive from their concomitant binding to multiple receptors. One strategy to
overcome these limitations is to target individual neurotrophin receptors — such
as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin
receptor or sortilin with small-molecule ligands [124, 125]. Application of
neurotrophic factors able to modulate neuronal survival and synaptic connectivity
is a promising therapeutic approach for AD. Ciliary neurotrophic factor (CNTF)
16 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
and/or CNTF receptor-associated pathways may have AD-modifying activity
through protection against progressive Abeta-related memory deficits [126].
Ciliary neurotrophic factor oral administration in 3xTg-AD and wild type female
mice was associated with significant reduction in abnormal hyperphosphorylation
and accumulation of tau at known major AD neurofibrillary pathology [127].
NSC can be derived from different primary tissues such as fetal, postmortem,
neonatal or adult brain tissues [109], or from ESCs and iPSCs [128 - 130]. In an
AD mouse model, the engrafted NSCs survived, differentiated into different
neuronal and glial elements, and improved learning and memory function [131,
132]. Transplantation of rat NSC in fimbria-fornix has been shown to improve
memory function, and to restore lost cholinergic neurons [133, 134].
The specific microenvironment (niche) of the recipient brain has been shown to
have a major impact on the proliferation and differentiation potential of the
engrafted NSCs. In this regard, it has been revealed that overexpression of human
amyloid precursor protein shifted the differentiation potential of the engrafted
NSCs to form more astrocytes than neurons or oligodendrocytes [135]. In
contrast, it was previously demonstrated that genetic engineering of NSC to over-
express nerve growth factor (NGF) helped promote proliferation and
differentiation of engrafted NSC. It was demonstrated that NSCs that are
genetically modified to stably express hNGF engrafted well into the cerebral
cortex of AD rats and enhanced different cognitive parameters; an effect that was
not show upon engraftment of non-genetically manipulated NSC [100].
NSCs have also been used as a vehicle for several amyloid-inhibitory genes such
as neprilysin, insulin degrading enzyme, plasmin, and cathepsin B [107].
Fibroblast-delivered neprilysin has been shown to reduce amyloid plaques in AD
mice [102, 136]. Engraftment of embryonic NSCs isolated from embryonic
medial ganglionic eminence (MGE) into the hippocampal hilus of aged apoE4-KI
mice (with or without accumulation) developed into mature inhibitory
interneurons and rescued learning and memory despite the toxic environment
created by amyloid-beta and apoE4 [137]. Such inhibitory GABAergic
interneurons could connect to more than thousands of excitatory neurons leading
to significant improvement of learning and memory functions [138, 139].
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 17
Several other cellular sources have been used to treat animal models of AD
pathology in addition to NSCs such as embryonic stem cells (ESCs), mesen-
chymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) and these
cells have been shown to be effective in removal of AD pathology. These cells
can improve the cognitive ability of animals [120, 133, 134, 140 - 146] by cell
replacement [140, 144], Aβ reduction [133, 134, 141, 142], neurotrophic action
[133], and immune modulation [122]. Following engraftments, ESCs, NSCs and
MSCs-derived from bone marrow have been shown to survive, migrate, and
differentiate into cholinergic neurons, restoring spatial learning and memory
ability for AD animal models [142].
Induced Pluripotent Stem Cell-Based Therapy for AD
De novo generation of neurons from iPSCs seems to be a promising approach for
AD treatment. New neurons generated from iPSCs from familial AD patients
exhibited positive MAP2 and β III-tubulin expression, normal electro-
physiological activity in vitro, and formed functional synaptic contacts. The
genetic background of AD patients from which iPSC-derived neurons originated
is reflected in the formed neurons, which displayed similar pathological features
[147]. This observation necessitates the final tuning of iPSC technology before
translation into AD patients. One possible way to alter the associated mutation is
the use of recent genome editing protocols to eliminated associated deleterious
AD variants.
Direct programming of somatic cells into functional neurons or induced neurons
(iN) seems to be a possibly effective protocol for AD cell-based therapy. The iN
might represent a direct source of replacement for lost neurons that are associated
with AD pathology. However, such direct differentiation protocols usually
provide low yields of non-proliferated, terminally differentiated neurons. The
lower cellular yield in this protocol might limit its broad application in cell-based
therapy for AD [148]. It is suggested that direct reprograming of somatic cells into
induced neural progenitor cell (iNPCs) which have the ability to differentiate into
all types of neural cells would be a potential promising therapeutic strategy for
AD pathology [149 - 151].
18 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
A major breakthrough in the field of stem cell-based therapy for AD has been
achieved in converting somatic cells into iNSCs using defined transcription
factors [152, 153]. The iNSCs elicited in this technique have been shown to share
similarities with NSC in proliferation, differentiation, and self-renewal
capabilities. The iNPCs were also obtained from mouse embryonic fibroblasts
using chemical cocktails under a physiologically hypoxic condition, without
overexpression of exogenous genes [154, 155]. Direct conversion of somatic cells
into iNPCs may well overcome the ethical issue associated with the collection of
cells from human embryos, and at the same time it should help to reduce the
tumorigenic nature of the iPSCs [154, 156].
Despite the apparent success in the direct reprogramming of somatic cells into iN,
and iNPSc which have proven to be able to give rise to all types of neural cells,
efficient induction of cholinergic neurons from NSC and iNPCs remains a
challenge. Under typical culture condition, the great majority of NSCs/NPSCs
seem to be converted into glial restricted states, with low efficiency for specific
neuronal subtypes [157]. Moreover, most of the transplanted NSCs/NPCs tend to
be converted into astrocytes, especially in response to injury [158, 159]. Based on
these observations, it seems plausible that using AD cell-based strategy that have
been primarily directed to produce specific neuronal subtypes, such as forebrain
cholinergic neurons, will be more effective, especially the apparent loss of
cholinergic neurons associated with AD pathology, and the selective degeneration
of septal and hippocampal GABAergic neurons reported in AD mouse models
[160]. Thus, direct conversion of somatic cells into GABAergic neuronal
progenitor seems to be a promising avenue for further exploration in strategies for
AD treatment.
One of the recently discovered protocols that might revolutionize the field of cell-
based therapy of AD is the direct in vivo conversion of somatic cells such as
astrocyte into region-specific iPNCs in the AD brain [161, 162]. These studies
will contribute to the conversion of active astrogliosis into neurogenesis, possibly
leading to the formation of disease specific neurons, such as forebrain cholinergic
neurons. Such novel therapeutic strategy could potentially overcome the need for
an invasive transplantation protocol, and also provide an effective tool for
personalized medicine.
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 19
Expert View and Future Perspectives
The amyloid cascade hypothesis is a relatively simple linear theory that relates
most if not all of the AD pathology to the pathological aggregation of amyloid
beta in brain regions known to be involved in learning and memory. Defective
APP breakdown products formed as result of mutations of key AD-related genes
may be at the core of AD pathology. Despite the central role of Aβ in the
initiation of AD pathology proposed in the amyloid cascade hypothesis, a number
of alternative mechanistic pathways of viewing the disease have been suggested,
such as progressive loss of integrity in the brain’s neuronal networks, gradual
decrease in synaptic density, increasing neuritic atrophy, and eventually widely
dispersed cell loss. Moreover, there is enough evidence to support that AD
represents a failure of autophagy and/or lysosomal function, loss of Ca2+
homeostasis due perhaps to excitotoxic activity. Other alternative causes include
failure of neuronal cell cycle control, neuroinflammation, progressive oxidative
damage that accumulates with age, DNA damage, loss of mitochondrial function
and general metabolic compromise. These have all been argued to be root causes
of the disease.
Amyloid is a frequent contributor to the AD disease process, however evidence
suggests that it is neither necessary nor sufficient. The biology of AD is perhaps
one of the most perplexing systematic malfunctions of the nervous system so far
known. Indeed, it is likely that we will need to address all of the listed options if
we are to cure AD or completely prevent it.
Cell-replacement therapy for AD has achieved some success in animal models of
AD. Although these preclinical studies are promising, many obstacles are required
to be addressed before successful translation into therapy for human AD patients
can be achieved. Different types of stem cells are used for testing cell-based
therapy in animal models of AD, such as embryonic, mesenchymal, and neural
stem cells, and recently induced pluripotent stem cells were included. These cells
are either engrafted without any genetic manipulation as naive wild type cells or
they are genetically engineered to overexpress specific biologically active
substances that can alter AD molecular pathways. At the preclinical level, most of
the engrafted cells survived, proliferated, and differentiated into different neuronal
20 FCDR-Alzheimer Disorder, Vol. 5 Marei et al.
subtypes, although the hostile environment of AD in many cases favors the
transformation of them into astrocytes rather than neurons. This caveat prompted
many investigators to directly reprogram somatic cells into specific cell types
such as the cholinergic neurons that are known to be lost in AD brain. The low
yield of differentiated neurons also prompted many investigators to find a
mechanism by which somatic cells could be transformed into neuronal progenitor
cells rather than fully differentiated neurons. Such approaches should enhance the
proliferative and differentiating features of the transformed cells to enhance the
ability to replace all of the lost neuronal and glial cell types.
Progress in the stem cell research field has also opened new windows to the
generation of region-specific and subtype-specific neural progenitors through
direct reprogramming from somatic cells, thus creating another new concept for
potential AD treatment. Moreover, instead of cell transplantation, directly
reprogramming of activated astrocytes already in the pathological site of AD brain
into region- or subtype-specific iNPCs by direct injection of defined factors
in vivo, could be a promising strategy. Development of comprehensive therapeutic
protocols for provision of different cell types and stages, together with anti-Aβ,
and anti-Tau antibodies will be a crucial step for clinical translational studies in
human AD patients.
CONFLICT OF INTEREST
The author confirms that he has no conflict of interest to declare for this
publication.
ACKNOWLEDGEMENTS
Authors would like to thank Qatar University Biomedical Research Center
(QUBRC), STDF: Grant # 99 (Egypt) for supporting stem cell research through
several funding grants. Authors would like to thank Mayo Clinic, Rochester,
Minnesota, USA for granting permisison to Dr Mohamed El Zowalaty and
providing parts of figures which were used with permission from Mayo
Foundation for Medical Education and Research.
Amyloid Cascade and Stem Cells in Alzheimer's Disease FCDR-Alzheimer Disorder, Vol. 5 21
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... Reanalysis of APP and PS mutations indicate that AD pathology is more closely associated with disturbances in the metabolism of APP and buildup of its C-terminal fragments, instead of Aβ generation and amyloid plaque formation [25]. Many trials to treat AD by targeting Aβ have been unsuccessful and the Aβ cascade hypothesis is unable to elucidate the multiplex process of AD pathology [26]. ...
... Free radicals generated during the progression of AD are scavenged by withanamides present in WS. Molecular modeling studies revealed that withanamides A and C exclusively bind with Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and inhibit the plaque development and thus blocks the neuronal cell death triggered by Aβ [115]. WS is a memory booster that also improves learning [116]. ...
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