Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease.

The pathology of Alzheimer's disease (AD) is featured with extracellular amyloid-β (Aβ) 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 Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca2+ influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD. [Display omitted] • Aβ plaque-associated tissues become rigid • Microglial Piezo1 senses stiffness of Aβ fibrils • Piezo1 facilitates microglial clearance of Aβ plaques • Pharmaceutical activation of microglial Piezo1 ameliorates brain Aβ burden Hu et al. identify that microglia sense Aβ fibril stiffness through the mechanosensory ion channel Piezo1, which regulates microglial response to Aβ plaques and limits Alzheimer's disease (AD)-like pathology in AD mice, which highlights a protective role of microglial mechanobiology in AD pathogenesis. [ABSTRACT FROM AUTHOR]