Mesenchymal stem cells enhance autophagy and increase beta-amyloid clearance in Alzheimer disease models

Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid- (A) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of A clearance In A-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with A only. Immunofluorescence revealed that MSC coculture in A-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in A-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with A-treated neuronal cells. Furthermore, MSC coculture markedly increased A immunoreactivity colocalized within lysosomes and decreased intracellular A levels compared with A-treated cells. In A-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of A in the hippocampus, which was elevated in A-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of A in AD models, which may lead to increased neuronal survival against A toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment.