Mechanotransduction Activates Microglia and Impairs Phagocytosis in Stiff Amyloid‐β Plaques

Abstract In Alzheimer's disease (AD), microglia are activated by mechanical and biochemical cues in the amyloid‐β (Aβ) plaque‐associated microenvironment, causing neuroinflammation. While the impact of Aβ stiffness on microglial activation and the dynamic interplay between inflammation and phagocytosis remain unclear. Here, an in vitro Aβ plaque‐associated microglia microenvironment model is built and investigated how the stiffness of Aβ plaques triggers microglial activation via the PIEZO1 mechanotransduction pathway. Scanning electrochemical microscopy and scanning ion conductance microscopy are employed to in situ monitor reactive oxygen species release, membrane permeability, and phagocytic activity of microglia. It is found that Aβ stiffness drives early microglial activation, forming an oxidative‐stressed microenvironment that impairs the membrane integrity of microglia. And the antioxidant‐resveratrol effectively improves the phagocytosis dysfunction of the impaired microglia. This work reveals the complex interplay among mechanical cues, neuroinflammation, and phagocytic dysfunction in microglia and suggests potential therapeutic strategies targeting microglial dysfunction in AD.