Mesenchymal Stem Cell Therapy and Alzheimer’s Disease: Current Status and Future Perspectives

Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease worldwide, but its cause remains unclear. Although a few drugs can provide temporary and partial relief of symptoms in some patients, no curative treatment is available. Therefore, attention has been focused on research using stem cells to treat AD. Among stem cells, mesenchymal stem cells (MSCs) have been used to treat the related pathologies in animal models of AD, and other neurodegenerative disease. This review describes latest research trends on the use of MSC-based therapies in AD and its action of mechanism. MSCs have several beneficial effects. They would be specified as the reduction of neuroinflammation, the elimination of amyloid-β, neurofibrillary tangles, and abnormal protein degradation, the promotion of autophagy-associated and blood-brain barrier recoveries, the upregulation of acetylcholine levels, improved cognition, and the recovery of mitochondrial transport. Therefore, this review describes the latest research trends in MSC-based therapy for AD by demonstrating the importance of MSC-based therapy and understanding of its mechanisms in AD and discusses the limitations and perspectives of stem cell therapy in AD.

Keywords

Alzheimer’s disease mesenchymal stem cells stem cell therapy

BACKGROUND

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder and is characterized by memory and cognitive dysfunctions. The National Institute on Aging (NIA) reported that more than 5.5 million Americans, most of whom were older than 65 years, might have AD-associated dementia (National Institute on Aging home page). According to the World Alzheimer Report, an estimated 50 million people suffered from dementia in 2019, and it was predicted that 152 million worldwide would have the disease in 2050. The estimated total cost of dementia was USD$1 trillion in 2019 and the cost could increase to around USD$2 trillion in 2030 [1].

In general, AD slowly progresses and its major symptoms are cognitive impairment and memory loss [2]. The disease starts with mild cognitive impairment and loss of short-term memory, but eventually results in severe dementia [3]. The symptoms are caused by neuronal loss in the hippocampus and cortex, which play important roles in learning, memory, and language. Brain size is reduced in AD patients due to neuron damage in the hippocampus and cortex [4].

As mentioned above, the etiology of AD has not been established, but aging, genetics, lifestyle, and environment are identified as major risk factors [5]. The aggregation of amyloid-β (Aβ) in the form of extracellular amyloid plaques and the hyperphosphorylation of tau are major hallmarks of AD [6]. Aβ peptides are derived from the cleavage of transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretases. Under normal conditions, Aβ monomers and oligomers are degraded by several peptidases including neprilysin and insulin-degrading enzyme. However, defective clearance of Aβ causes its accumulation and damage to synapses and neurons in the hippocampus and cortex under abnormal conditions, and eventually progresses into AD [7]. Tau is a microtubule-associated protein and one of the major phosphoproteins in brain. It is produced by neurons and localized in neuron cell bodies and axons. However, tau dysfunction induced by its hyperphosphorylation causes them to aggregate and form neurofibrillary tangles (NFTs) [8]. When abnormally hyperphosphorylated tau has aggregated, numbers of NFTs are increased and neuronal cell death follows [9]. Therefore, many researchers continue to try to develop means of preventing Aβ accumulation and tau hyperphosphorylation.

Currently, no curative therapeutics are available for AD. The current drugs such as galantamine, rivastigmine, and donepezil were developed to conserve the diminishing acetylcholine and only used to ameliorate some cognitive symptoms of AD. Therefore, the present review highlights the importance of stem cell-based treatments of AD and investigates the mechanisms of actions of mesenchymal stem cells (MSC)-based stem cell therapy.

HISTORY OF MSCs ON THERAPEUTICS OF AD

Stem cells are classified into MSCs, neural stem cells (NSCs), or induced pluripotent stem cells (iPSCs) based on site of origin, differentiation stage, and their properties. They all have been used in AD. Most are MSC-based therapy, while others utilize NSCs or iPSCs.

MSCs have been well demonstrated to be a potent cell source for stem cell therapy [10 –12]. They have four advantages. First, they can be obtained from various sources such as bone marrow, umbilical cord blood, adipose tissue, or dental pulp. Second, their differentiation potentials are superior to other stem cells. For example, they differentiate into neuronal cells, osteocytes, chondrocytes, or adipocytes when stimulated with proper growth factors [13 –16]. Third, they are relatively safe compared to totipotent embryonic stem cells (ESCs) or iPSCs and have relatively low risks differentiating into cancer cells. Fourth, MSCs are rarely immunogenic as they do not express MHC class II or co-stimulatory molecules (CD80, CD86, or CD40) [17], as well as suppress the activations and proliferations of T and B lymphocytes [18 –20], and the differentiations and maturations of dendritic cells [21, 22].

ACTION MECHANISMS OF MSCs IN AD (SUMMARIZED IN TABLE 1)

Table 1

Action mechanisms of MSCs in AD

Action mechanisms	Cell type	Animal model	Effects	Reference
Reducing neuro-inflammation	BM-MSCs	Senescence-accelerated mouse prone 8 mice model	•Decreases inflammatory factors (IL-1β, IL-6, and iNOS) and oxidative stress •Increases therapeutic factor (TGF-β)	[23]
	hUCB-MSCs	APP/PS1 mice model	•Reduces Aβ deposition and tau phosphorylation	[24]
			•Decreases inflammatory response (TNF-α, IL-1β, and BACE-1)
	MenSCs	APP/PS1 mice model	•Reduces Aβ plaque deposition and tau hyperphosphorylation	[25]
			•Induces alternatively activated microglia which enhances Aβ-degrading enzyme activity
	hMSCs		Increases IL-1 and G-CSF through IL-1R1 pathway	[26]
			•Decreases inflammatory mediators
	BM-MSCs	SE-induced cognitive and memory impairment rat model	Increases anti-inflammatory cytokines and growth factors (IL-10, G-CSF, PDGF-β, IL-6, and IL-2) •Decreases proinflammatory cytokines (TNF-α, IL-1β, MCP-1, SCF, MIP-1α, GM-CSF, and IL-12)	[27]
Microglial changes	BM-MSCs	APP/PS1 mice model	•Reduces pE3-Aβ plaque size in hippocampus	[29]
			•Decreases microglial size and numbers
			•Inhibits gene expression (TNF-α, IL-6, MCP-1, and NGF)
	WJ-MSCs	APP/PS1 mice model	•Reduces Aβ deposition	[30]
			•Increases anti-inflammatory cytokines (IL-10)
			•Decreases microglial activation and pro-inflammatory cytokines (TNF-α and IL-1β)
	MSCs		•Suppresses proinflammatory cytokines (TNF-α, IL-1β, IL-6, and iNOS) and enhances phagocytosis	[31]
			•Switches functional phenotypes in microglia
	pMSCs	Dementia rat model	•Improves cognitive dysfunction	[32]
			•Rescues acetylcholinesterase activity in the hippocampus
			•Inhibits microglial proliferation and activation
Aβ removal	WJ-MSCs	5×FAD mice model	•Increases proteasome activity	[33]
			•Decreases Aβ plaque deposition
	hUCB-MSCs	APP/PS1 mice model	•Induces Aβ-degrading enzyme neprilysin expression in microglia via sICAM-1/lymphocyte function-associated antigen-1 pathway	[34]
			•Reduces Aβ plaque in hippocampus
	hUCB-MSCs	APP/PS1 mice model	•Removes toxic Aβ plaque	[35]
			•Promotes hippocampal neurogenesis and synaptic activities through GDF-15 from hUCB-MSCs
	hUCB-MSCs	5×FAD mice model	•Secrets TSP-1, which promotes synaptic density via neuroligin-1 and α2δ-1 receptors	[36]
	hUCB-MSCs	APP/PS1 mice model	•Increases synapsin 1 levels and improves spatial learning and memory	[37]
			•Reduces Aβ deposition and soluble Aβ levels via Aβ-degrading enzymes neprilysin and insulin-degrading enzyme
			•Induces M2-like microglial activation which inhibits neuroinflammation
	BM-MSCs	AlCl₃-induced rat model	•Removes Aβ plaques in hippocampus	[38]
	BM-MSCs	Aβ-injected mice model	•Removes Aβ deposition •Modulates the microglial activity	[39]
	MSCs	APP/PS1 mice model	•Enhances autophagosome formation	[40]
			•Enhances Aβ degradation through autophagy
	hpMSCs	Traumatic brain injury mice model	•Decreases proinflammatory genes and increases anti-inflammatory, anti-oxidant, and angiogenesis-related genes	[41]
			•Inhibits the astrocytes and microglia activation
			•Reduces Aβ accumulation
NFT removal	BM-MSCs		•Rescues cell viability of AT tau cells	[42]
			•Promotes neuritogenesis in the AT tau cells
	hUCB-MSCs	APP/PS1 mice model	•Reduces Aβ deposition, BACE-1 levels, and tau hyperphosphorylation	[24]
			•Decreases microglia-induced proinflammatory cytokines and increases anti-inflammatory cytokines
			•Improves spatial memory dysfunction
	MenSCs	APP/PS1 mice model	Improves spatial learning and memory	[25]
			•Ameliorates Aβ and tau hyperphosphorylation via anti-inflammatory factors with changes in microglia phenotypes
Ubiquitin proteasome system and abnormal protein degradation	WJ-MSCs	5×FAD mice model	•Increases proteasome activity •Decreases Aβ plaque deposition	[33]
Functional recovery of autophagy	BM-MSCs	Vascular dementia rat model	•Increases BDNF and NR1 protein expression levels in the hippocampal CA1 region	[48]
			•Decreases autophagy-related protein expression levels (p62, LC3II, and Beclin 1)
			•Improves learning and memory function
	MSCs	APP/PSEN1 mice model	•Enhances autophagosome formation •Enhances Aβ degradation through autophagy	[40]
BBB function recovery with endothelial cells	BM-MSCs		•Increases von Willebrand factor, VE-cadherin, and VEGFR-2 expression •Differentiates into functional endothelial cells	[50]
	MSCs	2×Tg AD mice model	•Restores learning and memory deficits	[51]
			•Increases VEGF and the clearance of Aβ protein
Sphingolipid metabolism	BM-MSCs	Niemann-Pick type C mice model	•Increases sphingosine-1-phosphate levels and decreases sphingosine	[55]
			•Inhibits apoptosis through altering calcium homeostasis
	AD-MSCs		•Inhibits LPS-induced microglial activation and proliferation	[56]
Increases in acetylcholine level	AD-MSCs	Aged mice model	•Improves locomotor activity and cognitive function	[57]
			•Restores acetylcholine levels
	Hp-MSCs	Dementia rat model	•Improves cognitive dysfunction	[32]
			•Rescues acetylcholinesterase activity in the hippocampus
			•Inhibits microglial proliferation and activation
Recovery of mitochondrial transport	MSCs	Ischemic rat model	•Transfers of mitochondria from MSCs to neural cells, which restores the bioenergetics of the recipients’ cells and stimulates proliferation	[59]
	MSCs	Cisplatin-induced cognitive impairment mice model	•Cisplatin, induced by MSCs-derived mitochondria, decreases NSCs death and mitochondrial membrane potentials •Prevents DCX⁺-NPCs loss in hippocampus	[60]

Reducing neuroinflammation

Active inflammatory reactions are known to underlie the pathological mechanism of AD, and MSC transplantation has been reported to ameliorate brain inflammation by regulating inflammatory and/or therapeutic factor secretion [23 –27]. Here we review five milestone studies. Li et al. transplanted bone marrow-MSCs (BM-MSCs) into bone marrow cavities in a senescence-accelerated mouse prone 8 animal model, and demonstrated the beneficial effects. The levels of inflammatory factors (IL-1β, IL-6, iNOS, and HO-1) were reduced, and the level of TGF-β (a therapeutic factor) was increased, which improved inflammatory status, decreased oxidative stress, and improved cognitive function [23]. When human umbilical cord blood-MSCs (hUCB-MSCs) were intracerebrally transplanted into the APP/PS1 mouse model, microglia decreased the secretions of inflammatory factors and increased therapeutic factors to improve inflammatory status [24]. In the case of human menstrual blood-derived stem cells (MenSCs) transplantation into the cerebellum of an APP/PS1 mouse model, they activated microglia and caused them to secrete anti-inflammatory factors via an alternative neuroprotective phenotype [25]. Redondo-Castro et al. demonstrated when microglial BV2 cells were activated with bacterial lipopolysaccharide (LPS) and then treated them with BM-MSCs, BM-MSC-treatment upregulated the expressions of anti-inflammatory and neuroprotective factors (IL-10, VEGF, BDNF, G-CSF, NGF, and IL-1Ra) [26]. Finally, when MSCs were injected intranasally into a rat model of AD, they reduced levels of inflammatory factors (IL-1β, IL-12, TNF-α, and IFN-γ) in hippocampus [27].

Microglia changes

Reactive microglia are responsible for protein clearance in brain under chronic inflammatory conditions, but their small surface areas limit uptakes of extracellular proteins and their abilities to remove proteins. In addition, reactive microglia induce astrocytes to adopt harmful reactive forms and increase oxidative stress by activating neurotoxic oxygen and nitrogen species [28]. When Aβ accumulates in brain, microglia try to restore brain functions by absorbing proteins and secreting anti-inflammatory factors. However, chronic microglial activation increases microglia numbers and the expression of inflammatory factors and decreases protein clearance.

Many authors have reported that stem cell injections in mouse models of AD inhibit microglia activation and reduce inflammatory factor levels in brain [29 –32]. When BM-MSCs were transplanted into an APP/PS1 mouse model of AD via tail vein, microglial numbers in cortex, microglia sizes, and pro-inflammatory factor levels (TNF-α and IL-6) were reduced [29]. Likewise, Wharton’s Jelly-derived MSCs (WJ-MSCs) transplantation into an APP/PS1 AD mouse model via tail vein, reduced reactive microglia numbers and levels of pro-inflammatory (IL-1β and TNF-α) factors, and increased IL-10 (anti-inflammatory factor) levels [30]. Furthermore, expressions of inflammatory factors were downregulated, an alternative activated phenotype of microglia was induced, and phagocytosis was improved in primary rat microglia cultured in rat MSCs conditioned media. In addition, TGF-β secreted by MSCs blocked the nuclear factor-κB pathway and restored the TGF-β pathway [31]. Cho et al. reported when human placenta-MSCs (pMSCs) were intracerebroventricularly or intravenously injected into an AD rat model, AD-associated increases in microglia numbers in brain lesion rapidly returned to normal levels [32].

Amyloid-β removal

The Aβ plaque is a representative characteristic of AD. Stem cell transplantation has shown to reduce Aβ plaque levels by reducing microglia numbers, activating proteasomes, and enhancing autophagy and β-amyloidase secretion [33 –41]. β-amyloidase exhibits Aβ-degrading activity such as insulin degrading enzyme. In detail, agouti-related peptide secreted by MSCs increased proteasome activity and decreased Aβ plaque [33]. Soluble intracellular adhesion molecule-1 (sICAM-1) secreted by hUCB-MSCs induced the expression of neprilysin (a Aβ-degrading enzyme) [34]. Growth differentiation factor-15 (GDF-15) secreted by hUCB-MSCs was found to reduce Aβ plaques and promote hippocampal neurogenesis [35]. Furthermore, thrombospondin-1 (TSP-1) secreted by hUCB-MSCs restored neuronal synaptic density impairment caused by Aβ [36]. Yang et al. transplanted hUCB-MSCs-derived neuron-like cells into bilateral hippocampus in Aβ-induced AD model and observed they activated microglia, promoted the secretions of anti-inflammatory substances, reduced Aβ accumulation, and restored memory deficits [37]. In an AD rat model with hippocampal Aβ lesions, a single intravenous injection of BM-MSCs resulted in the complete elimination of Aβ [38]. In a mouse model of acute AD, bilateral hippocampus injections of BM-MSCs removed Aβ by activating microglia [39]. Shin et al. observed intravenous administration of MSCs improved lysosome-autophagy and removed Aβ by activating autophagy-associated LC3-II and BECN1/Beclin 1 [40]. When traumatic brain injury was induced, Aβ plaques aggregated in the mouse model. pMSCs were intravenously double-injected at 4 and 24 h post-injury onto the traumatic brain injury mice model, and reduced infarct sizes, inflammatory, oxidative responses, and inhibition of Aβ plaque formation were observed [41].

Neurofibrillary tangle removal

NFTs are formed when Aβ induces the hyperphosphorylation of tau and cause cytotoxicity and cell death. Numerous stem cell therapies have been shown to prevent tau hyperphosphorylation-induced cytotoxicity [24 , 42]. Zilka et al. treated cells containing mutated tau proteins with rat MSCs or their secreted substances; as a result, cell death was reduced and metabolic activity improved, but tau expression was unaffected. The authors suggested that the cytotoxic effect of modified tau in AD can be reduced by MSCs [42]. When hUCB-MSCs [24] or MenSC [25] were transplanted into cerebellum of APP/PS1 mouse model, rapid reduction of tau hyperphosphorylation, increase of anti-inflammatory factor levels, and changes on microglial phenotype were observed.

Ubiquitin proteasome system and abnormal protein degradation

Trypsin-like activity (proteolytic activity) of proteasomes is significantly lower and the activity of immunoproteasomes is significantly higher in neurons from AD patients than in those of normal subjects [33]. To recover ubiquitin proteasome system function in AD, Lee et al. administered agouti-related peptide secreted from MSCs or WJ-MSCs to mouse hippocampi and observed a significant increase in proteasome activity and a decrease in ubiquitin-conjugated protein accumulation [33].

Functional recovery of autophagy

Under normal conditions, autophagy plays an important role in maintaining cellular homeostasis by breaking down unnecessary or abnormal cellular components; however, dysfunctions in autophagy are associated with cancer, inflammatory, and neurodegenerative diseases [43, 44]. Interestingly, Guan et al. showed autophagy plays an important role in maintaining stemness, stem cell expansion, and differentiation [45]. Another study performed by Salemi et al. noted autophagy levels were elevated in human skin and blood-derived MSCs and important for maintaining stemness [46]. Furthermore, the activation of autophagy via Bcl-xL is known to promote MSC survival and differentiation [47].

Relatively less studies have been performed on the relationship of autophagy and AD. Wang et al. transplanted MSCs into tail vein in a rat model of vascular dementia and found that levels of autophagy proteins of LC3-II and Beclin-1 were significantly increased, which indicated autophagy was associated with AD [48]. Upon MSC transplantation, synaptic damage, mitochondrial agglomeration, and damaged presynaptic area were reduced and the hippocampal expressions of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate receptor 1 were increased, leading to improved cognitive function [48]. When MSCs were injected through the tail vein in a mouse model of AD, it significantly enhanced autolysosome formation and Aβ clearance [40].

BBB function recovery with endothelial cells

On normal condition of the blood–brain barrier (BBB), drugs can be delivered to brain via carrier-mediated transport or receptor-mediated transcytosis. However, various BBB dysfunctions are observed in the cortex and hippocampus of AD patients. Examples are capillary leakage and infiltration of blood cells, pericyte degeneration, endothelial degeneration, and microvessel reduction and shortening [49]. BBB breakdown leads to accumulation of neurotoxic materials and the activations of astrocytes and microglia and inflammatory response [49], leading to accumulation of the fibrous scraps of cells such as pericyte and endothelial cells, which make drug absorption or therapeutic delivery to the brain difficult. Therefore, BBB recovery is required for successful drug transport and healthy vascular endothelial cells need to be introduced for BBB recovery.

MSCs and iPSCs have been differentiated into endothelial cells to recover BBB functions, and this differentiation has shown to play key roles in the regeneration of blood vessels. MSCs can be differentiated into endothelial cells with differentiation media containing vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin like growth factor (IGF), epidermal growth factor (EGF), ascorbic acid, and heparin [50]. In an APP/PS1 mouse model, BM-MSC transplantation increased VEGF expression level and improved endothelial dysfunction and synaptic plasticity [51]. Moreover, several studies have successfully used stem cells to induce vascular regeneration and functions of vascular endothelial cells for treating ischemic diseases, and this technique could be useful for treating AD.

Sphingolipid metabolism

Upon AD progression, sphingolipid metabolic abnormalities are often observed. It is associated with dysfunctional protein clearance, impaired lysosome production and inflammatory control functions, and Aβ production as well as autophagy functions [52 –54]. Two experiments were conducted to explore the possibility of using stem cells on sphingolipid metabolic abnormalities in AD [55, 56]. BM-MSCs were transplanted into cerebellum of a Niemann-Pick type C disease mouse model and corrected increased sphingosine-1-phosphate levels and decreased sphingosine accumulation were observed. Therefore, it could reduce apoptosis, restore calcium homeostasis, and prevent neuron loss [55]. In another study, conditioned medium from adipose tissue-derived MSCs controlled sphingosine kinase/sphingosine-1-phosphate signaling, and led to the suppression of microglial activation [56].

Increases in acetylcholine level

Acetylcholine is a neurotransmitter and mainly involved in learning, cognition, and memory function. In AD patient, its levels are significantly lower, and these reductions are associated with cognitive impairment. Studies have shown MSC therapy can restore brain acetylcholine levels, followed by restoring cognitive function [32, 57]. In aged mice, the intracerebroventricular administration of human adipose tissue-derived MSCs improved locomotor activity, cognitive function, and acetylcholine levels in brain tissue [57]. In detail, MSCs differentiated into neurons or astrocytes and choline acetyltransferase proteins were produced, which increased acetylcholine synthesis and restored neuron integrity. In a rat model of dementia with 192 IgG-saporin administrations, pMSCs were transplanted via cerebroventricular or tail vein and resulted in a rapid decrease in acetylcholinesterase activity and improved cognitive functions [32].

Recovery of mitochondrial transport

Decreased mitochondrial quality due to aging or chronic inflammatory conditions produces various changes and increases the risk of AD. Reduced ATP production in impaired mitochondria causes malfunctioning of the ubiquitin/proteasome and lysosomal systems, which require ATP. In addition, impaired mitochondria cannot properly defend against oxidative stress induced by oxygen or nitrogen species. Furthermore, these mitochondrial dysfunctions can cause neurotoxicity. Neuronal mitochondrial quality is maintained by astrocytes [58]. In the presence of severe neuronal mitochondria damage, healthy mitochondria are transported by adjacent astrocytes to damaged neurons via tunneling nanotubes. However, in chronic inflammatory conditions, this role of astrocytes diminishes and the proportion of activated astrocytes increases, leading to astrogliosis, thereby neuronal mitochondrial quality fail to be restored by astrocytes, which could cause AD.

When astrocytes are exposed to ischemic damage caused by reactive oxidative stress, mitochondrial transport from intravenously transplanted MSCs to astrocytes restores neuronal bioenergetics and proliferation. Babenko et al. revealed the importance of the mitochondrial motor protein Rho-GTPase 1 in mitochondria transport in a middle cerebral artery occlusion rat model [59]. Another study reported loss of DCX⁺ neural progenitor cells in the hippocampal dentate gyrus and subventricular zone are relieved by MSC intranasal administration [60].

OTHER EFFECTS OF STEM CELL THERAPIES ON AD (SUMMARIZED IN TABLE 2)

Table 2

Other effects of stem cell therapies

Action mechanisms	Cell type	Animal model	Effects	Reference
Regulation of hippocampal neurogenesis	MSCs	Aβ-injected mice model	•Increases hippocampal neurogenesis and differentiates mature neuron from NPCs via Wnt signaling pathway	[62]
	NSCs	APP/PS1 mice model	•Improves spatial learning and memory function	[63]
			•Enhances expression of synaptic proteins (SYN &GAP43)
Paracrine effects	hUCB-MSCs	Aβ-injected rat model	•Improves spatial learning and memory function and neurogenesis	[66]
			•Increases acetylcholine and ChAT expression and activation of astrocytes and microglia
			•Reduces Aβ expression
	hUCB-MSCs	5×FAD mice model	•Secrets TSP-1, which promotes synaptic density via neuroligin-1 and α2δ-1 receptors	[36]
	hUCB-MSCs	APP/PS1 mice model	•Removes toxic Aβ plaque	[35]
			•Promotes hippocampal neurogenesis and synaptic activities through GDF-15 from hUCB-MSCs
	hUCB-MSCs	APP/PS1 mice model	•Induces Aβ-degrading enzyme neprilysin expression in microglia via sICAM-1/lymphocyte function-associated antigen-1 pathway	[34]
			•Reduces Aβ plaque in hippocampus
	pMSCs	Dementia rat model	•Improves cognitive dysfunction	[32]
			•Rescues acetylcholinesterase activity in the hippocampus
			•Inhibits microglial proliferation and activation
EVs	BM-MSCs	SE-induced cognitive and memory impairment rat model	•Increases anti-inflammatory cytokines and growth factors (IL-10, G-CSF, PDGF-β, IL-6, and IL-2)	[27]
			•Decreases proinflammatory cytokines (TNF-α, IL-1β, MCP-1, SCF, MIP-1α, GM-CSF, and IL-12)
	BM-MSCs	Ischemic mice model	•Increases endothelial cell angiogenesis via activating VEGFR1, VEGFR2, AKT, and ERK	[70]
			•Recovers blood flow in ischemic hindlimbs

Regulation of hippocampal neurogenesis by stem cells

Neurogenesis is a process whereby NSCs form new neurons in the subgranular zone of the hippocampal dentate gyrus and in the subventricular zone of lateral ventricles. Alterations in neurogenesis occur during the early stage of AD and result in neuronal loss in the hippocampus and cognitive dysfunction [61]. Several reports have shown stem cell therapy has beneficial effects on neurogenesis against AD. Oh et al. found MSC transplantation into tail vein increased hippocampal neurogenesis and enhanced differentiation from NPCs to mature neurons in an AD mouse model via the Wnt signaling pathway [62]. Zhang et al. reported NSCs transplantation improved cognitive dysfunction and the expressions of synaptic proteins (e.g., synaptophysin and growth-associated protein-43), indicating the presence of synaptogenesis in an APP/PS1 AD mouse model [63]. In another study, it was reported granulocyte colony stimulating factor increased neurogenesis and improved memory and neurobehavioral function in an Aβ-induced rat model of AD [64]. These results indicate stimulation of neurogenesis offers a strategy for the treating AD.

Paracrine effects of stem cells

When stem cells are transplanted, they secreted proteins to the surrounding environment referred as paracrine effects [65]. Several paracrine proteins such as BDNF, NGF, TSP-1, GDF-15, and sICAM-1 are secreted by transplanted stem cells in brain [34–36 , 66]. BDNF derived from hUCB-MSCs promoted neurogenesis, reduced Aβ, inhibited neuronal apoptosis, and improved learning and memory in AD rats [66]. TSP-1 secreted by hUCB-MSCs attenuated Aβ-induced synaptic dysfunction [36], and secreted GDF-15, which promotes adult hippocampal neurogenesis and synaptic activity [35]. In addition, sICAM-1 derived from hUCB-MSCs was found to increase the expressions of neprilysin that eliminates Aβ [34]. It is anticipated that various paracrine compounds would be identified with their anti-inflammatory and nerve regenerating effects. Cho et al. provided more evidence about paracrine effect of MSC transplantation in a rat model of dementia. After intracerebroventricular or intravenous transplantation, acetylcholinesterase activity rapidly decreased and cognitive functions improved. However, acetyltransferase activity did not increase at sites of pMSC administration, which suggested pMSCs might not differentiate into cholinergic neurons, but rather differentiate to cholinergic neurons by the paracrine effect [32].

Extracellular vesicles (EVs)

The importance of EVs derived from membrane of stem cells is also being explored [67]. EVs include exosomes and microvesicles, which are membrane-contained vesicles derived from cells. In addition, EVs also contain not only protein, but also other substances like lipids and genetic materials (RNA, DNA) [68]. EVs containing various substances can be secreted and transferred to other cells or used to control the surrounding microenvironment. EVs can be transferred to target cells through the BBB without being degraded in blood because they are surrounded by a lipid bilayer [69]. The importance of EVs derived from stem cells as drug delivery systems is emerging.

EVs secreted by BM-MSCs were administered intrathecally to a pilocarpine-induced rat model. A1-exosomes, which is one of the EVs and has anti-inflammatory effects in the spleen, reached the hippocampus within 6 h of administration. Animals exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in hippocampus [27]. In another study, MSC-derived EVs enhanced ischemic tissue recovery and angiogenesis by activating the receptors of the angiogenic genes VEGFR1 and VEGFR2 [70].

NSCs therapy

NSCs exist in lateral ventricles of the subventricular and subgranular zones of the dentate gyrus [71]. They can be obtained either isolated from fetal or human brain or differentiated from ESCs or iPSCs. NSCs can differentiate into neuronal or glial lineage depending on the growth factors, which are relatively safe for cell therapy and reported to secrete various factors of interest for neuronal therapy [72].

Extensive research has demonstrated the protective and regenerative effects of NSCs [73]. In a rat model of AD, transplantation of NPCs promoted cognitive recovery and new synapse generation [74]. It was also reported intrahippocampal transplantation of NPCs improved cognitive deficits by increasing BDNF-mediated synaptic density and axonal outgrowth of hippocampus in 3×Tg AD mice [75]. Another study demonstrated that intrahippocampal transplantation of NPCs attenuated cognitive deficits and neuroinflammation by reducing glial activation and TLR4-mediated inflammatory mediator levels in an APP/PS1 mouse model [76]. These studies demonstrated NPCs-based therapy has therapeutic effects in animal models of AD. Transplantation of human NSCs into lateral ventricles in a mouse model of AD resulted in decreased hyperphosphorylation of tau and suppressed microgliosis and astrogliosis via a Trk-dependent Akt/GSK3β signaling [77].

When NSCs were edited to overexpress choline acetyltransferase (F3. ChAT NSCs), which plays an important role in the synthesis of acetylcholine and transplanted into ICR mice, ChAT enzyme expression, acetylcholine levels, and cholinergic nervous system marker expressions were upregulated, and cognitive function and physical activities were markedly improved [78].

iPSCs therapy

iPSCs are pluripotent stem cells reprogrammed from somatic cells with four transcription factors (Oct4, Sox2, Klf4, and c-Myc) [79 –81]. iPSCs can be used as disease modeling or cell source for transplantation after differentiation into neurons [82]. Patient-derived iPSCs are useful because they enable the pathological phenotypes of diseases to be observed. For example, iPSCs are prepared from somatic cells of AD patients and then differentiated into neurons or glia, or used to create brain organoids. It is also reported that the progression of AD was observed on normal human iPSCs when they were transplanted into the brains of AD mice [83].

Autogenic iPSCs-derived cells do not elicit immune responses and can generate numerous neurons from their self-renewal ability. On degenerative neurological diseases, they have been used to compensate for neuronal loss. Some evidence indicates that iPSCs-based therapy has beneficial effects in animal models of neurodegenerative disease. For example, neuronal precursors derived from human iPSCs were conducted stereotactic transplantation and found to improve spatial memory dysfunction in a human APP Tg mouse model [84]. It was also reported that additional transcription factors differentiated from iPSCs into dopaminergic neuron-like cells, suggesting therapeutic potential in Parkinson’s disease [85]. Another study reported stereotactic transplantation of NSCs derived from human iPSCs showed therapeutic effects in a mouse model of ischemic stroke by reducing pro-inflammatory factor levels and attenuating BBB damage [86].

LIMITATIONS OF STEM CELL THERAPY AND PROBLEMS TO BE SOLVED

There are substantive preclinical studies that demonstrate promising effects in AD treatment, and researchers are continuing to reveal potential therapeutic mechanisms. However, the safety of stem cell delivering system has not been established yet and there are several limitations of stem cell therapy. First, long-term survival and phenotypic stability of stem cell-derived neurons or glial cells in the graft after transplantation are not desirable. For example, a patient with ataxia telangiectasia was transplanted NSCs, and he was diagnosed with multifocal brain tumor after four years [87]. Schmidt et al. reported that NSC transplantation could adversely induce tropism toward brain tumors by tumor-upregulated VEGF and angiogenic-activated microvasculature [88]. Second, a small number of transplanted stem cells could fail to differentiate or choose the wrong way that form tumors. Teratoma, which is a tumor comprised of organized tissues representing all three germ layers, is a major concern limiting stem cell therapy. Teratomas have been produced by stem cell transplantation into testis [89], kidney [90], liver [91], and hind leg muscle [92]. It has also been reported that teratoma formation increases dose-dependent manner after transplanting ESCs into heart in mice [93]. To overcome this limitation, in most studies 10³–10⁷ stem cells are transplanted for inhibiting teratoma formation [89 , 95]. Third, there is a big limitation in AD research in that current animal models do not adequately mimic human AD pathology. Although many clinical trials of stem cell therapy have been conducted based on animal studies of stem cell transplantation, positive clinical results are not always promised [96]. To overcome these limitations, researchers are trying to develop an appropriate preclinical model with 3D brain organoids derived from human iPSCs. Iwashita et al. reported that 3D brain organoid derived from iPSC of AD patients are better able to mimic the human AD pathology than current animal models. They established dorsal cortical neurons derived from iPSCs using high intensity (1500 Pa) collagen gel, indicating the possibility to regulate the differentiation of stem cells into specific types of neurons [97]. Establishment of 3D organoids in various conditions may be ready for unpredictable interactions between transplanted cells and host neurons. Stem cell therapy has many advantages, but the limitations still exist. Therefore, profound research is required to resolve the issues presented above.

PERSPECTIVES OF STEM CELL THERAPY IN AD

Various AD-associated factors induce a chronic inflammatory state in the brain, which leads to Aβ accumulation, tau hyperphosphorylation, and neuronal cell death. Given that dementia progresses over time, AD therapy requires treatments that address pathologic mechanisms relevant at different stages of disease progression (Fig. 1). For example, patients with an inflammatory brain condition in the early stage should be treated to prevent the establishment of a chronic inflammatory condition. If the stage is in progress of inflammation associated with Aβ accumulation before tau hyperphosphorylation and cognitive impairment have yet to appear, at such a stage, it might be more effective to employ paracrine molecules from stem cells therapy that promote the secretion of Aβ degrading enzymes and neurogenesis. If AD has progressed to tau hyperphosphorylation and cognitive dysfunction, NSC and MSC transplantation-based therapeutic strategies should be considered. From a research perspective, it is essential that we identify the substances secreted by stem cells at different disease stages.

Fig.1

Overview of the therapeutic effects of MSC therapy on AD pathology. This figure summarizes our review. The AD brain affects several mechanisms of AD pathology such as chronic inflammation, microglial changes, Aβ plaques, NFT formation, abnormal sphingolipid metabolism, decreased synapses and acetylcholine levels, mitochondrial dysfunction, and cognitive impairment. On the other hand, MSC therapy confers therapeutic effects on these AD pathological changes. AD, Alzheimer’s disease; Aβ, amyloid-β; BBB, blood-brain barrier; MSC, mesenchymal stem cells; NFT, neurofibrillary tangles; VEGF, vascular endothelial growth factor.

Since clinical symptoms of cognitive impairment and memory dysfunction occur after tau hyperphosphorylation and NFT formation, blocking Aβ accumulation and tau hyperphosphorylation are required. In addition, the relationship between somatic mutation and tau hyperphosphorylation in hippocampus should be determined [77]. If associations between genetic mutations and AD are elucidated, stem cell-based gene therapy for AD and dementia might be possible.

Stem cell therapy has significant advantages over chemotherapeutic based strategies. In particular, stem cells are likely to produce therapeutic effects even if their specific pathological and molecular mechanisms are not determined. This is because stem cells that act in response to factors they secrete or are present in the environment may prove therapeutically effective without knowledge of the mechanisms involved, as has been shown recently for probiotics. However, the broad-spectrum influences of stem cells are also a cause of concern. Accordingly, comprehensive studies and clinical studies are required to evaluate the safety of stem cell therapy in order to enable the treatment of patients likely to realize meaningful benefits. Nevertheless, we believe that stem cell therapy could provide one of the approaches in resolving problems presented by AD.

Footnotes

ACKNOWLEDGMENTS

This study was financially supported by the [2019 Post-Doc. Development Program] of Pusan National University. This work was also supported by the National Research Foundation of Korea (Grant no. 2018R1D1A1B07043493).

Authors’ disclosures available online ().

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