Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Summary The pathology of Alzheimer’s disease (AD) is associated with the extracellular amyloid-β (Aβ) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of Aβ fibrils. The upregulation of Piezo1 in Aβ plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of Aβ plaques, resulting in the exacerbation of Aβ and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain Aβ burden and cognitive impairment in the 5×FAD mouse. Together, our results reveal Piezo1, as a mechanosensor of Aβ fibrils stiffness in microglia, could represent a promising therapeutic target for AD.