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

ABSTRACT

Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-ß (Aß) 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 Aß clearance In Aß-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aß only. Immunofluorescence revealed that MSC coculture in Aß-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 Aß-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aß-treated neuronal cells. Furthermore, MSC coculture markedly increased Aß immunoreactivity colocalized within lysosomes and decreased intracellular Aß levels compared with Aß-treated cells. In Aß-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 Aß in the hippocampus, which was elevated in Aß-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 Aß in AD models, which may lead to increased neuronal survival against Aß 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.