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

Alzheimer's disease (AD) is associated with the formation of extracellular amyloid-β (Aβ) plaque, perturbing the mechanical properties of brain tissue. Microglia sense and integrate biochemical and mechanical cues in their local microenvironment, intimately linked with AD progress. However, little is known about how microglial mechanosensing pathways are implicated in AD pathogenesis. Gene Ontology (GO) analysis of the significantly down-regulated genes in Piezo1 conditional knockout microglia revealed a significant functional reduction in synapse organization, cell-substrate adhesion, and cytoskeleton system-based events (morphogenesis, migration, and endocytosis) in 5×FAD mice. 1. 5×FAD mice were crossed with Cx3cr1CreER-EYFP; Piezo1fl/fl mice to develop Cx3cr1CreER-EYFP; Piezo1fl/fl; 5×FAD. Cx3cr1CreER-EYFP; Piezo1fl/fl; 5×FAD and Piezo1fl/fl; 5×FAD male littermates aged at 4.5 weeks were subjected with four daily intraperitoneal 20 mg/kg tamoxifen to generate microglial Piezo1 knockout in 5×FAD mice (Piezo1MGKO; FAD) and the control littermate mice (Piezo1fl/fl; FAD); 2.Microglia isolation from adult mouse brain of Piezo1MGKO; FAD and Piezo1fl/fl; FAD. RNA were extracted from the indicated groups for RNA profiles.