PM2.5 exposure exacerbates Alzheimer's disease pathology through lysosomal dysfunction in APP/PS1 mice

Ambient fine particulate matter (PM2.5) is a key environmental risk factor closely associated with Alzheimer's disease (AD), although its specific molecular mechanisms remain incompletely elucidated. In this study, APP/PS1 double transgenic AD mice and their wild-type (WT) littermates were used as research subjects. A chronic exposure model was established via nasal instillation of PM2.5 for 90 consecutive days to systematically investigate the effects of PM2.5 on the pathological progression of AD. Behavioral assessments demonstrated that chronic PM2.5 exposure significantly induced cognitive impairment in WT mice and exacerbated cognitive deficits in AD model mice, suggesting that PM2.5 has universal neurotoxicity. Pathological analyses further revealed that PM2.5 exposure exacerbated neuropathological changes in AD mice, manifested as significantly increased β-amyloid (Aβ) plaque deposition and enhanced tau protein hyperphosphorylation. Mechanistic investigations identified PM2.5-induced lysosomal dysfunction as a critical factor that led to dysregulation of Aβ-metabolizing proteins (e.g., PS1), thereby disrupting normal Aβ metabolism and exacerbating Aβ pathology. Concurrently, lysosomal dysfunction activated microglia, triggering neuroinflammatory responses and inducing myelin sheath damage in the hippocampus and cortex, which further disrupted the homeostasis of the neural microenvironment and aggravated Aβ pathology. In summary, this study confirms that PM2.5 exposure accelerates AD pathological progression through the synergy of multiple pathways, including lysosomal dysfunction, PS1 upregulation, neuroinflammation, and myelin damage, with lysosomal dysfunction playing a core driving role. These findings not only provide new insights into the association between PM2.5 and AD but also lay a crucial theoretical foundation for the development of targeted preventive and therapeutic strategies for AD.