Functional Mechanism of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Animal Models with Alzheimer's Disease: Inhibition of Neuroinflammation

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 mechanisms remain to be determined. Available data demonstrate transplanted BMMSCs can inhibit neuroinflammation, which may be related to microglial M1/M2 polarization and is regulated by the secretion of autocrine and paracrine cytokines. BMMSCs also mitigate Aβ plaques and Tau tangles in the brain, which may be associated with the recruitment of peripheral blood monocytes and the subsequent comprehensive effects. The therapeutic effects of stem cells involve potential mechanisms such as immunomodulation, apoptosis, and proliferation. BMMSC-mediated functional reconstruction through dynamic remodeling develops a novel balance. Herein, present review recapitulates the molecular basis of BMMSC-assisted biological processes and summarizes the possible mechanisms related to the interaction between BMMSCs and microglia. The transplanted BMMSCs can suppress neuroinflammation that plays a key role in the pathogenesis of Alzheimer's disease.

Keywords: Alzheimer’s disease; apoptosis; bone marrow-derived mesenchymal stem cells; immunomodulation; microglia.

Graphical abstract

Figure 1

Apoptosis mechanism in Alzheimer’s disease. Extracellular Aβ proteins and inflammatory cytokines (eg, TNF-α, IL-1β) can cause neuronal apoptosis through membrane receptors. The interruption of intracellular homeostasis induces apoptosis via intrinsic pathway as evidenced by oxidative stress and the hyperphosphorylated aggregates of microtubule-associated protein Tau in neurofibrillary tangles. The release of cytochrome c leads to apoptosome formation, which results in caspase activation and subsequent apoptosis. Pro-survival Bcl-2 proteins block the mitochondrial pathway of apoptosis. Endoplasmic reticulum (ER) stress induces apoptosis by initiating calcium-signaling and caspase activation. Inhibitors of apoptosis proteins (IAPs) regulate apoptosis by binding and inhibiting caspases. Mitochondrial Smac/Diablo and Omi/HtrA2 can bind to IAPs to facilitate caspase activation and apoptosis.

Figure 2

Potential mechanisms of stem cell therapy. The pathological basis of Alzheimer’s disease is neuronal death and the impairment of synaptic transmission, which are concomitant with aberrant Aβ deposits. The transplantation of stem cells derived from bone marrow, adipose tissue, amnion, umbilical cord, or embryonic tissue inhibits neuroinflammation, removes Aβ proteins, and attenuates Tau pathology in the lesion of AD. The comprehensive effect of different mechanisms alleviates neuropathology and improves cognitive deficits in animal models with Alzheimer’s disease.

Figure 3

Stem cell therapy induces the inhibition of neuroinflammation and recruitment of peripheral blood monocytes. The transplantation of stem cells leads to the secretion of the autocrine and paracrine factors, which recruits peripheral blood monocytes into the lesion of Alzheimer’s disease. The activated monocytes can accelerate the elimination of aberrant Aβ proteins. Recruited monocytes may facilitate microglial M1/M2 polarization. Neuroinflammation can be inhibited by transplanted stem cells. Immunoregulation participates in functional reconstruction through dynamic remodeling.

Figure 4

The establishment of new balance mechanism. Under physiological conditions, there is a dynamic equilibrium between the production and elimination of Aβ peptides. If the intrinsic homeostasis is altered, the excessive accumulation of extracellular Aβ proteins results in pathological changes, as shown in the pathogenesis of Alzheimer’s disease. Autocrine and paracrine cytokines are secreted subsequent to the transplantation of BMMSCs, which regulate inflammatory/immune processes. The transplantation of stem cells is key regulator for the establishment of new balance mechanism.