Mesenchymal stem cell–derived exosomes ameliorate Alzheimer's disease–related cognitive impairment in APP/PS1 mice via SIRT1–FOXO1-mediated autophagy

Background Mesenchymal stem cells (MSCs) have therapeutic potential for Alzheimer’s disease (AD); however, their neuroprotective mechanisms remain incompletely understood. This study aimed to determine whether human umbilical cord–derived MSCs (hUC-MSCs) and hUC-MSC-derived exosomes (Exos) exert protective effects against AD-like pathology in APP/PS1 mice by modulating SIRT1–FOXO1-mediated autophagy. Methods We used specific-pathogen-free female APP/PS1 transgenic mice and wild-type C57BL/6J mice. The mice were divided into the wild-type control group, APP/PS1 model group, hUC-MSC group, Exos group, and recombinant SIRT1 protein group. Mice in the hUC-MSC, Exos and recombinant SIRT1 protein groups received tail vein injections of hUC-MSCs (1 × 10 6 cells in 0.4 mL suspension), Exos, or recombinant SIRT1 protein, respectively, once weekly for 4 weeks. Mice in the wild-type control and APP/PS1 model groups were administered an equal volume of sterile saline via the tail vein. The Morris water maze test was performed to evaluate cognitive function. In vitro models of AD-like pathology were established by exposing SH-SY5Y cells to lipopolysaccharide (LPS) and amyloid-β (Aβ). Pharmacological interventions with EX-527 and chloroquine were used to examine SIRT1 involvement and autophagy dependence. Western blotting and co-immunoprecipitation assays were used to assess protein levels and protein associations, respectively. Results Exosome treatment produced modest, marginally significant ( p = 0.071) improvements in cognitive performance in APP/PS1 mice, whereas hUC-MSC treatment showed only a favorable trend toward ameliorating spatial learning and memory deficits. Western blotting revealed that hUC-MSCs and Exos increased hippocampal levels of SIRT1, FOXO1, BECN1, and LC3B and decreased those of Aβ and p62. Similar molecular alterations were observed in LPS/Aβ-exposed SH-SY5Y cells. Co-immunoprecipitation identified an association between SIRT1 and FOXO1. In vitro pharmacological experiments supported the involvement of SIRT1-associated autophagy in exosome-mediated Aβ reduction. Exosomes reproduced partial neuroprotective effects of hUC-MSC treatment. Conclusions hUC-MSC-derived exosomes can reduce Aβ levels and confer limited cognitive benefits in AD models. The findings support the involvement of SIRT1–FOXO1-associated autophagy and suggest that exosome-mediated paracrine signaling contributes to hUC-MSC-mediated neuroprotection.