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Review
. 2022 Mar 3;13(1):90.
doi: 10.1186/s13287-022-02765-8.

The functional mechanism of bone marrow-derived mesenchymal stem cells in the treatment of animal models with Alzheimer's disease: crosstalk between autophagy and apoptosis

Chuan Qin  1 , Lin Bai  1 , Yongning Li  2 , Kewei Wang  3
Affiliations
Review

The functional mechanism of bone marrow-derived mesenchymal stem cells in the treatment of animal models with Alzheimer's disease: crosstalk between autophagy and apoptosis

Chuan Qin et al. Stem Cell Res Ther. .

Abstract

The transplantation of bone marrow-derived mesenchymal stem cells (BMMSCs) alleviates neuropathology and improves cognitive deficits in animal models with Alzheimer's disease. However, the underlying mechanism remains undefined. Based on meta-analysis and comprehensive review, high-profile studies support the theory that transplanted BMMSCs activate autophagy, as evidenced by the expression levels of signal molecules such as Beclin-1, Atg5, LC3-II, and mTOR. Functional autophagy mitigates neuronal apoptosis, which is reflected by the alterations of IAPs, Bcl-2, caspase-3, and so forth. Moreover, the transplantation of BMMSCs can decrease aberrant amyloid-beta peptides as well as tau aggregates, inhibit neuroinflammation, and stimulate synaptogenesis. There is a signal crosstalk between autophagy and apoptosis, which may be regulated to produce synergistic effect on the preconditioning of stem cells. Forasmuch, the therapeutic effect of transplanted BMMSCs can be enhanced by autophagy and/or apoptosis modulators.

Keywords: Alzheimer’s disease; Apoptosis; Autophagy; Bone marrow-derived mesenchymal stem cells.

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Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Alzheimer’s disease and neuronal apoptosis. Apoptosis is conducted through intrinsic and extrinsic pathways in the pathogenesis of Alzheimer’s disease. Inflammatory cytokines, such as TNFα, IL-6 and IL-1β, can trigger the neuronal apoptosis through membrane receptor or extrinsic pathway (i.e., TNFα/caspase-8/caspase-3). The intrinsic pathway of neuronal apoptosis is activated by intracellular insults including tau aggregates, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, free radicals, etc. Mitochondrial cytochrome c (Cyt c) is released to initiate apoptosis signaling through the Cyto c/caspase-9/caspase-3 cascade. The pathological manifestations of Alzheimer’s disease depend on the comprehensive effect of diverse mechanisms. There is a complicated network to modulate the development of Alzheimer’s disease. The red line represents inhibitory effect. Bcl-2, B-cell lymphoma 2; IL-1β, interleukin-1β; ROS, reactive oxygen species
Fig. 2
Fig. 2
Secretion of autocrine and paracrine cytokines is induced by the transplanted BMMSCs. These factors have diverse functions. For instance, IL-4 and IL-10 can suppress inflammatory role and exert positive effect. GM-CSF recruits peripheral monocytes into the lesion. These monocytes are further activated by extracellular Aβ proteins, which accelerate Aβ clearance in APP/PS1 mice. TGF-β participates in multiple signaling pathways to mediate amyloid metabolism, immunoregulation, and neuroprotection. The comprehensive effect of functional autocrine and paracrine cytokines determines the therapeutical potential of BMMSC
Fig. 3
Fig. 3
Apoptosis plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ plaques were accumulated in the hippocampus of APP/PS1 mice, which induced neuronal apoptosis (A). The meta-analysis demonstrated that the transplantation of BMMSCs could decrease the level of soluble Aβ proteins (B) and inhibited the activation of caspase-3 (C)
Fig. 4
Fig. 4
Synergistic effect of stem cell therapy with autophagy activation. The transplantation of BMMSCs stimulates autophagy and inhibit apoptosis, which improves memory and cognitive function in animal models with Alzheimer’s disease. When the transplanted BMMSCs is combined with drug regulators, it is hypothesized that a better therapeutic effect can be acquired
Fig. 5
Fig. 5
Interaction between autophagy and apoptosis. The downregulation of autophagy causes neural apoptosis. Autophagy is able to accelerate apoptosis via the degradation of IAPs as well. Apoptosis inhibits autophagy in enzyme-dependent manners. There is signal crosstalk between apoptosis and autophagy by sharing common regulators such as p53, Atg5, caspase-8, Beclin-1/Bcl-2, and IAPs. IAPs, inhibitors of apoptosis proteins; Bcl-2, B-cell lymphoma 2; Cyto c, cytochrome c; c-FLIP, cellular FLICE-like inhibitory protein; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; AKT or PKB, protein kinase B; mTOR, mammalian target of rapamycin; ATG5, autophagy related 5; LC3, microtubule-associated proteins 1A/1B light chain 3B; p53, tumor protein P53; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
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