Novel Balance Mechanism Participates in Stem Cell Therapy to Alleviate Neuropathology and Cognitive Impairment in Animal Models with Alzheimer's Disease.

Stem cell therapy improves memory loss and cognitive deficits in animal models with Alzheimer's disease. The underlying mechanism remains to be determined, but it may involve the interaction of stem cells with hippocampal cells. The transplantation of stem cells alters the pathological state and establishes a novel balance based on multiple signaling pathways. The new balance mechanism is regulated by various autocrine and paracrine cytokines, including signal molecules that target (a) cell growth and death. Stem cell treatment stimulates neurogenesis and inhibits apoptosis, which is regulated by the crosstalk between apoptosis and autophagy-(b) Aβ and tau pathology. Aberrant Aβ plaques and neurofibrillary tau tangles are mitigated subsequent to stem cell intervention-(c) inflammation. Neuroinflammation in the lesion is relieved, which may be related to the microglial M1/M2 polarization-(d) immunoregulation. The transplanted stem cells modulate immune cells and shape the pathophysiological roles of immune-related genes such as TREM2, CR1, and CD33-(e) synaptogenesis. The functional reconstruction of synaptic connections can be promoted by stem cell therapy through multi-level signaling, such as autophagy, microglial activity, and remyelination. The regulation of new balance mechanism provides perspective and challenge for the treatment of Alzheimer's disease.