Stem Cell Therapies for Alzheimer's Disease: Is It Time?

Sheng-Min Wang; Chang-Uk Lee; Hyun Kook Lima


Curr Opin Psychiatry. 2019;32(2):105-116. 

In This Article

Stem Cells for Alzheimer's Disease and Its Mechanism

Stem cells can be defined according to their potency, or their potential to differentiate into different cell types:[17] totipotent cells (e.g. morula or first few divisions of a fertilized egg) can potentially develop into any human cell;[18] pluripotent cells (e.g. blastocyst) to all three germ layers;[19] multipotent cells to multiple specialized cell types present in a specific tissue or organ (e.g. hematopoietic stem cells to all blood cells) and oligopotent cells to few cell types within a tissue or organ (e.g. lymphoid cell to B and T cells, but not red blood cells);[20] and unipotent cells to only their own cell type (e.g. progenitor cells, such as muscle satellite cells).[21] Stem cells can also be classified according to their origin and cell types. In terms of origin, embryonic stem cells (ESC), placental or umbilical cord blood stem cells (UCBSC), and induced pluripotent stem cells (IPSC) are widely studied. Regarding cell types, neural stem cells (NSC) and mesenchymal stem cells (MSC) are often investigated.[22] A summary of stem cells commonly used in Alzheimer's disease therapy are provided in Table 1.

Classification Based on Cell Origin

ESCs are derived from the inner cell mass of a blastocyst with pluripotency.[23] A previous study showed that ESCs can improve spatial learning and memory in Alzheimer's disease rats by differentiating into basal forebrain cholinergic neurons and γ-aminobutyric acid (GABA) interneurons.[24] Clinical translation of ESCs has been limited because of high teratoma formation risk. Aberrant immune reaction and rejection are other important limitations of ESCs. Moreover, ethical controversies must be clarified before they can be utilized in FDA-approved clinical trials.[25]

Umbilical cord blood is remnant blood of a postdelivery placenta and umbilical cord. The cord blood is rich in hematopoietic stem cells and other stem cells, such as MSCs.[26] Previous studies of UCBSCs (mostly MSCs) suggested that they might improve spatial learning and prevent memory decline. Numerous mechanisms, including reduction of Aβ plaques, BACE, and tau hyperphosphorylation, in addition to microglial neuroinflammation reversal and anti-inflammatory cytokine promotion, were proposed.[27] Although ethical concerns exist, especially regarding commercial cord blood banks, they are the most common source of stem cells used for Alzheimer's disease research because of the relative ease of harvest and handling if harvest is performed after normal delivery.[28,29]

IPSCs, technologies pioneered by Shinya Yamanaka's lab in Japan, are pluripotent stem cells that can be directly programmed from adult cells by over expressing transcription factors.[30] A previous study showed that it was possible to direct human fibroblasts to differentiate into specific neurons (e.g. dopaminergic neurons).[31] Furthermore, more recent research showed that intra-hippocampal transplanted human IPSCs in Alzheimer's disease mice successfully survived, differentiated into mature cholinergic neurons, and reversed spatial memory impairment.[32] IPSCs are adult stem cells, so ethical concerns could be resolved. However, because the technology behind IPSCs is complex, and data are scarce, numerous other issues must be resolved. Immune rejections could be reduced by using autologous IPSCs, but transplanted autologous IPSCs displayed phenotypic neuropathology, including abnormal Aβ levels, elevated tau phosphorylation, reduced neurite length, and altered electrocompetency.[33–35]

Classification Based on Type of Cell

NSCs are self-renewing, multipotent ( cells that can differentiate into all types of central nervous system (CNS) cells including astrocytes, microglia, oligodendrocytes, and neurons.[36] They may be an ideal candidate for Alzheimer's disease treatment because of their low propensity to cause tumor formation and immune reactions.[37] A previous study demonstrated that fibroblasts could be converted directly into neurons by forced expression of three lineage-determining transcription factors (Brn2, Ascl1, and Myt).[38] Transplanted mouse NSCs improved cognitive function by secreting brain-derived neurotrophic factor (BDNF);[39] additional suggested mechanisms of NSCs include attenuating neuroinflammation, decreasing Aβ and tau abnormality, and promoting neurogenesis and synaptogenesis in animal Alzheimer's disease models.[40–43] Factors limiting use of NSCs include their relative scarcity in human brain tissue and harvesting and handling difficulties.[44]

MSCs are the most frequently studied stem cell type because of their abundance, accessibility, ease of handling, and multipotency.[45] Animal studies suggest that MSCs express surface markers, such as CD44, CD63, CD105, and CD146 with a multilineage differentiation capacity through self-renewal.[37] Moreover, MSCs delivered intravenously were shown to successfully migrate to regions of neural injury without inducing a tumorigenic or immune response after crossing blood–brain barriers.[46] Extensive studies have illustrated their pro-cognitive effects based on diverse therapeutic mechanisms,[47] such as neuroprotection,[48] reduction of Aβ deposits and tau-related cell death,[49] and by decreasing pro-inflammatory cytokines (TNF-α and IL-1β) and increasing anti-inflammatory cytokines (IL-10).[27] Notable drawbacks include limited lineage and survival, short half-lives after transplantation and infiltration into multiple organs.[46]

Mechanism of Action Based on Animal Models

Alzheimer's disease is a multifactorial neurodegenerative disorder with multiple pathological processes.[50] Likewise, previous studies proposed diverse action mechanisms of stem cells in improving cognitive function of Alzheimer's disease. Important mechanisms included promoting neuronal regeneration and synaptogenesis, decreasing Aβ and tau disorder, and enhancing neuroprotective and anti-inflammatory effects.[51] Recent research has focused on the interplay of Aβ (and tau), neurons, and glia (Figure 2 a).[52,53] The amyloid cascade hypothesis posits that amyloid precursor protein (APP) is first cleaved by BACE then by γ-secretase-releasing Aβ peptides, which become oligomers, fibrils and finally, plaques. The Aβ plaques cause direct neuronal damage and synaptic loss resulting in cognitive dysfunction.[54] The Aβ oligomers further induce formation, monomerization, and oligomerization of the Aβs. Accumulated Aβs trigger a neuroinflammatory state including activation of pro-inflammatory microglia and reactive astrocytes.[55] Aβs cause morphological and functional transformation of microglia (the native macrophages of the CNS), from a ramified and anti-inflammatory (healthy or resting) state to an amoebic and pro-inflammatory (detrimental or active) state. Anti-inflammatory microglia cause aberrant phagocytosis of synaptic material and induce neuroinflammation by secreting inflammatory cytokines (e.g. tumor necrosis factor-α, interferon-γ, interleukin 1β), which leads to direct neuronal damage and synaptic loss. Inflammatory cytokines and Aβs activate resting astrocytes to become reactive astrocytes,[56] which have increased levels of APP, BACE, and γ-secretase, which further worsen the amyloid cascade. They also secrete pro-inflammatory mediators, which cause neuronal and synaptic damage and aggravate the Aβ formation and cascade.

Figure 2.

Possible mechanism of action of stem cells in treatment of Alzheimer's disease. (a) Data from [52–54]. aInflammatory cytokines include tumor necrosis factor-α, tumor growth factor-β, interferon-γ, interleukin-1β, and interleukin-6 others. ACh, acetylcholine; APP, Amyloid precursor protein; Aβ, amyloid-β; 1: amyloid cascade resulting in Aβ plaques; 2: Aβ oligomers further induces monomerization, and oligomerization of Aβ; 3: Aβ induces pro-inflammatory microglia and reactive; 4: pro-inflammatory microglia secretes inflammatory cytokines inducing more reactive astrocytes and Aβ formation; 1–4: all result in neuronal death and synaptic loss. (b) Data from [57,58]. Stem cells (1) induce regeneration of neuron and synapsis; (2) prevent pro-inflammatory microglia and promotes anti-inflammatory microglia leading to degradeing of Aβ and blockage of Aβ cascade; (3) inhibit astrogliosis and promotes nonreactive astrocyte, which enhances neuronal repair and synaptogenesis and phagocytize Aβ; (1–3) result in promotion of healthy neuron and synapsis.

Stem cells can induce direct regeneration of neurons and synapses, prevent formation of pro-inflammatory microglia and promote formation of anti-inflammatory microglia. Healthy microglia degrade Aβs by direct phagocytosis and by secreting proteolytic enzymes, which inhibit the amyloid cascade. In addition, anti-inflammatory microglia enhance neuroprotection by secreting neuroprotective factors (e.g. NGF and BDNF). Stem cells also inhibit astrogliosis and promote nonreactive astrocytes, which can regain vital functions including repairing injured neurons, enhancing synaptogenesis, and phagocytizing and breaking down Aβs instead of aggravating the Aβ cascade as reactive astrocytes do[51,57,58] (Figure 2 b).