Piezo1 facilitates microglial clearance of A¥â plaques
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Pharmaceutical activation of microglial Piezo1 ameliorates brain A¥â burden
Summary
The pathology of Alzheimer¡¯s disease (AD) is featured with extracellular amyloid-¥â (A¥â) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of A¥â-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in A¥â-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of A¥â fibrils and subsequently induced Ca2+ influx for microglial clustering, phagocytosis, and compacting of A¥â plaques. Microglia lacking Piezo1 led to the exacerbation of A¥â pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain A¥â burden and cognitive impairment in 5 ¡¿ FAD mice. Together, our results reveal that Piezo1, a mechanosensor of A¥â fibril stiffness in microglia, represents a potential therapeutic target for AD.