Alzheimer’s disease (AD) is a neurodegenerative disease that leads to atrophy throughout the brain including the basal forebrain cholinergic system, amygdala, hippocampus and several other cortical areas.
β-amyloid plaques and tau neurofibrillary tangles are hallmark features of AD. [16,18] Current therapies are limited to provide only partial and temporary improvement of AD symptoms.[15] Stem cell therapy can provide various ways to treat the cognitive dysfunction of AD. Transplantation of stem cell or stem cell-derived cells could enhance the cognitive function of the brain with AD. The cognitive decline induced by the degeneration of basal forebrain cholinergic neurons could be prevented by transplanting cholinergic neurons generated from neural stem cells (NSCs) in vitro. Alternatively, the stem cells could be used for the delivery of factors which can modify the course of the disease, as the stem cells can be genetically modified and have migratory capacity after transplantation.[15] There are limitations to the potential of stem cell therapies for AD. Stem cells reside in specialized microenvironments within the adult brain, and this microenvironment is a key factor in the therapeutic potential of stem cell therapy. Knowing the mechanisms underlying the neurogenic microenvironments for neurogenesis is necessary for the stem cell therapy of AD to reach its true potential. In addition, stem cell therapies involving cell grafting may not be applicable for certain cases of AD, in which the neurodegeneration is widespread. This is mainly due to cell grafting being able to target only local ares of the brain.[18]

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1.0 Neural stem cell transplantation | 1.1 Controlled generation of functional basal forebrain cholinergic neurons | 1.2 Neural precursor cell/neural progenitor cell transplantation | 1.3 Mesenchymal stem cell transplantation

1.0 Neural stem cell transplantation

Cell replacement of neural stem cell-derived cholinergic neurons

Therapeutic effects of NSC transplantation in the animal model of AD is mainly due to cell replacement of NSCs-derived cholinergic neurons. NSC transplantation into the basal forebrain of AD mice induces cholinergic neuron differentiation, and rescued the spatial learning and memory deficits.[19] Trophic action of glial cells and astrocytes increases the long-term survival of differentiated human NSCs, however they
do not have significant contribution in improving spatial learning and memory improvement, and cholinergic neuron differentiation.[8,19]

Brain-derived neurotrophic factor-mediated cognitive improvement

The mechanism of NSC transplant-induced improvement in spatial learning and memory involves brain-derived neurotrophic factor (BDNF). NSC-induced cognitive improvement is accompanied by increase in hippocampal synaptic density and BDNF level.[2] NSC-derived cells elevate hippocampal BDNF, and this in turn leads to increased synaptic density and recovery of hippocampal-dependent cognition. This process proceeds without altering Aβ or tau pathology. BDNF is an essential factor in NSC-induced cognitive improvement, and the recovery of cognition does not occur without BDNF.[2]


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Figure 1.0 NSCs increase synaptic density and produce BDNF in 3xTg-AD mice



Proton magnetic resonance spectroscopy for quantitative analysis of therapeutic effect of NSC transplantation

Proton magnetic resonance spectroscopy (1H-MRS) can provide an effective quantitative analysis of therapeutic effect of NSC transplantation in transgenic animal model of AD. 1H-MRS evaluates the metabolite changes in the hippocampal area before and after NSC transplantation.[3]


1.1 Controlled generation of functional basal forebrain cholinergic neurons


A significant loss of basal forebrain cholinergic neurons (BFCN) is a common feature of AD, and this is accompanied by deficits in spatial learning and memory. Selectively controlling the differentiation of human embryonic stem cells (hESCs) into BFCN could lead to enhanced cell replacement therapy. [1] BMP9 signaling in hESC-derived forebrain precursor cells induces expression of Lhx8 and Gbx1 in AD mice. These transcription factors are both necessary and sufficient to drive the differentiation of hESCs into functional BFCN. The ability to selectively control the differentiation of hESCs into BFCN is important for both understanding mechanisms regulating BFCN lineage commitment and the development of both cell transplant-mediated therapeutic interventions for AD.[1]


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Figure 1.1 Neuronal differentiation into BFCN with different transcription factors




1.2 Neural precursor cell/neural progenitor cell transplantation


Neural progenitor cells attenuate inflammatory reactivity/neuronal loss

Transplanted neural progenitor cells migrate to the hippocampal region of increased β-amyloid (Aβ) in response to increased level of Aβ in animal model of AD. The neural progenitor cells dramatically reduce the extent of microgliosis and the level of proinflammatory cytokine tumor necrosis factor-α (TNF-α). Neuronal progenitor transplantation is also effective in providing neuroprotection, recovering significant number of neurons.[17] Lack of neuronal viability marker microtubule associated protein-2 (MAP-2) associated with the neuronal progenitor cells suggests that mechanism underlying the neuroprotection may not be a cell replacement. These findings suggest that neuralprogenitor cell transplantation attenuates Aβ-induced inflammatory reactivity and provides neuroprotection.[17]


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Figure 1.2 Effects of NPC transplantation on inflammatory reactivity


Focal neural precursor cell implantation results in glial cell differentiation leading to recovery of cortical neurons

Transplanted neural precursors and astrocytes provide strong neuroprotection to dysfunctional tau protein-induced cortical neurodegeneration in the AD mice. Focal neural precursor cell implantation induces glial cell differentiation marked by flial fibrillary acidic protein (GFAP), and this in turn results in effective neuroprotection of cortical neurons.[5] The exact mechanism of neuroprotection is unknown and it was revealed that it is not a cell replacement, as there is no evidence of neuronal differentiation associated with the transplanted neural precursor cell. Predominant astrocytic and glial differentiation of transplanted neural precursor cells indicates that the neuroprotective effect of neural precursor cell is glial dependent.[5]


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Figure 1.3 NPC transplantation-induced neuroprotection within the superficial cerebral cortex




1.3 Mesenchymal stem cell transplantation


Efficient processing of β-amyloid by neuroectodermally converted mesenchymal stem cell

Neuroectodermal conversion of human adult mesenchymal stem cells (MSCs) induces a strong up-regulation of both F-spondin and neprilysin in AD mice. F-spondin and neprilysin are involved in the formation and degradation of Aβ peptides respectively. These mesenchymal-derived NSC-like cells (mNSCs) also express high levels of apolipoprotein E (APOE),[4] which promotes proteolytic degradation of Aβ peptides.[7] MSCs may be useful vehicles for delivering anti-Aβ activity, depicting a causal stem cell-based therapeutic approach to treat AD.[4]

Bone marrow-derived mesenchymal stem cell transplantation reduces β-amyloid deposition and recovers memory deficits

Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation reduces Aβ deposition in the cortex and hippocampus of AD mice dramatically. BM-MSC transplantation prevents the formation of deposition and removes the Aβ deposits in the brain. BM-MSC treatment increases the microglia population in the central nervous system (CNS). This effect of reducing Aβ deposits and increasing microglia activation are BM-MSC specific.[13] Microglia secrete proteolytic enzymes that degrade Aβ, such as insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase 9 (MMP-9) and plasminogen.[14,20] Furthermore, microglia also expresses receptors that promote the clearance and phagocytosis of Aβ, such as class A scavenger receptor, CD36 and receptor for advanced-glycosylation endproducts (RAGE).[6] Microglia can restrict senile plaque formation by phagocytosing Aβ. As AD mice age, their microglia become dysfunctional and exhibit a significant reduction in expression of their Aβ-degrading enzymes and Aβ-binding receptors. BM-MSC treatment restores this reduced expression of Aβ-degrading enzymes and increases expression of certain Aβ-binding receptors.[13] BM-MSC treatment also activates alternative microglial phenotype and these microglia cells elicit a neuroprotective effect. In addition, BM-MSC transplantation can reduce tau hyperphosphorylation in a pattern similar to aggregated Aβ. BM-MSC treatment ameliorates spatial learning and memory impairments associated with the accumulation of Aβ peptide.[13] These findings depict BM-MSC as a potential therapeutic agent for AD.


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Figure 1.4 BM-MSCs stimulate microglial activation



Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces β-amyloid plaques

Transplantation of human umbilical cord blood-derived MSC (hUCB-MSC) reduces Aβ deposits in vivo in AD mice.[11,12] hUCB-MSCs reduce Aβ42 via induction of neprilysin (NEP) induction. Soluble intracellular adhesion molecule-1 (sICAM-1) derived from hUCB-MSCs induces the expression of NEP in microglia and reduces Aβ42 levels.[9] sICAM-1 is identified as a paracrine factor released by hUCB-MSCs for NEP induction. ICAM-1-induced NEP expression could be regulated by the integrin-β2 lymphocyte function-associated antigen (LFA-1)-mediated signaling pathway. Neuroprotective effects of hUCB-MSCs were mediated by the sICAM-1-induced NEP expression.[9] It was revealed that transplantation of hUCB-MSCs induces NEP expression in vivo as well. In addition, transplantation of hUCB-MSCs reduces Aβ plaques in vivo.[9] hUCB-MSC transplantation decreases Aβ plaques via NEP expression of microglia. Study by Kim, JY., et al. reveals that Aβ plaques in remote cortices from the hippocampus were also reduced dramatically. Furthermore, migrating hUCB-MSCs were often observed near Aβ deposits in brain tissues. When hUCB-MSCs were inoculated in the hippocampus or the CSF in normal mice, there was no migration of hUCB-MSCs. These results indicate that Aβ plaques located remotely from injection sites could be removed by migration of hUCB-MSCs toward Aβ deposits.[9] hUCB-MSC-derived sICAM-1 decreases Aβ plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway.[9]


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Figure 1.5 Transplantation of hUCB-MSCs induces NEP expression in microglia




References:
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  2. Blurton-Jones, M., //et al//. (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. //PNAS// 106(32):13594-13599
  3. Chen, S., //et al//. (2012) H-MRS Evaluation of Therapeutic Effect of Neural Stem Cell Transplantation on Alzheimer’s disease in AβPP/PS1 Double Transgenic Mice. //JAD// 28(1):71-80
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  13. Lee, J.K., //et al//. (2010) Intracerebral Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Amyloid-Beta Deposition and Rescues Memory Deficits in Alzheimer’s Disease Mice by Modulation of Immune Responses. //Stem Cells// 28(2):329-343
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