Secreted endogenous macrosomes reduce Aβ burden and ameliorate Alzheimer's disease

Innovative therapeutic strategies are urgently needed for Alzheimer's disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extra -cellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited beta-amyloid (A beta) aggregation and rescued cells from A beta misfolding-induced cy-totoxicity. Furthermore, macrosome administration reduced A beta plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted A beta aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuropro-tective proteins that inhibit A beta misfolding. In particular, the small integral membrane protein 10-like protein 2B in macrosomes has been shown to inhibit A beta aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.