Microglia-derived extracellular vesicles mediate fine particulate matter-induced Alzheimer's disease-like behaviors through the miR-34a-5p/DUSP10/p-p38 MAPK pathway.

Fine particulate matter (PM2.5), a major component of air pollution, poses significant global health risks. Epidemiological studies have correlated long-term PM2.5 exposure and neurological disorders, including Alzheimer's disease (AD). Extracellular vesicles (EVs) are recognized as critical mediators of intercellular communication. Understanding the role of microglia EVs in neuronal dysfunction is essential, given the increasing awareness of non-cell-autonomous neurotoxicity. The mechanisms through which microglia and their EVs mediate PM2.5-induced neurotoxicity are poorly understood. This study demonstrated that PM2.5 exposure drives microglial toward the pro-inflammatory M1 phenotype, impairing the brain's immune defenses. PM2.5-treated microglia secrete miR-34a-5p-enriched EVs. These EVs are delivered to neurons, target DUSP10, activate the p-p38 MAPK pathway, increase aberrant tau phosphorylation and pathological Aβ proteins, and induce neuronal apoptosis in the hippocampus and cortical regions. These pathological changes contribute to cognitive and behavioral deficits in PM2.5-exposed mice. Knocking down miR-34a-5p in EVs from PM2.5-treated microglia rescued these phenotypes, mitigating AD-like pathology in mice. Our study identified miR-34a-5p as a critical regulator of neuro apoptosis and AD-like cognitive impairment induced by PM2.5 exposure. These findings underscore the pivotal role of microglial EVs in mediating intercellular communication between glia and neurons, providing valuable insights into the mechanisms underlying PM2.5-induced neurotoxicity.