Human breast milk-derived extracellular vesicles alleviate Alzheimer’s disease phenotypes through delivering CD36

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease that is the most common cause of dementia globally. To date, multiple types of extracellular vesicles (EVs), particularly those derived from stem cells, have been implicated to improve AD pathology, but the clinical applications of stem cell-derived EVs are restricted due to ethical/religious concerns, supply constraints, and other challenges. Here we found that human breast milk-derived extracellular vesicles (HM-EVs) mitigated AD pathology and rescued cognitive decline of 5xFAD mice, a preclinical mouse model of AD. We identified CD36, a microglial anti-Aβ receptor as the key cargo to mediate the therapeutic effects of HM-EVs by enhancing microglial phagocytosis and Aβ clearance. Moreover, blockage of CD36 using a monoclonal antibody abolished HM-EVs-driven Aβ phagocytosis of microglia, therefore aggravating cognitive performance and pathological changes of 5xFAD mice. Together, our findings indicate HM-EVs as a novel intervention strategy of AD through delivering CD36.