Alzheimer's disease (AD) is a neurodegenerative disorder driven by β-amyloid (Aβ) deposition, neuroinflammation, oxidative stress and metabolic dysregulation, with the latter as a central pathological hub. hucMSC-derived exosomes (hucMSC-exosomes) show therapeutic potential for AD, but their metabolic remodeling mechanisms remain unclear. We combined behavioral tests, pathological assays and untargeted metabolomics to investigate the neuroprotective effects and mechanisms of hucMSC-exosomes in APP/PS1 AD mice. Seven-month-old male APP/PS1 mice were randomly divided into AD-vehicle and AD-hucMSC-exosome groups, with age-matched C57BL/6 mice as wild-type controls. All mice received tail vein injections for 6 weeks. Morris Water Maze tests revealed that hucMSC-exosomes significantly improved spatial learning and memory in AD mice. Pathological analyses confirmed that hucMSC-exosomes reduced cerebral Aβ deposition, suppressed hippocampal pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and restored antioxidant capacity (SOD, GPx, GSH/GSSG). Untargeted metabolomic analysis of brain tissues revealed that 6 primary carbon, 8 primary nitrogen and 3 secondary metabolites were common differential metabolites across the two comparison cohorts (AD-vehicle vs. WT, AD-hucMSC-exosome vs. AD-vehicle), and their aberrant expression in AD mice was all reversed by hucMSC-exosomes. KEGG enrichment analysis showed that hucMSC-exosomes largely reversed dysregulated metabolic pathways in AD, including lipid, amino acid, nucleotide metabolism and autophagy/mitophagy. Collectively, hucMSC-exosomes ameliorate AD pathological phenotypes and cognitive deficits, an effect accompanied by metabolic homeostasis remodeling through cascades of reduced Aβ deposition, suppressed neuroinflammation and alleviated oxidative stress. Metabolic remodeling represents a prominent correlative feature of the neuroprotective effects of hucMSC-exosomes, providing candidate molecular targets for metabolically targeted AD therapy.
