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While the impact of A\u03b2 stiffness on microglial activation and the dynamic interplay between inflammation and phagocytosis remain unclear. Here, an in vitro A\u03b2 plaque\u2010associated microglia microenvironment model is built and investigated how the stiffness of A\u03b2 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 A\u03b2 stiffness drives early microglial activation, forming an oxidative\u2010stressed microenvironment that impairs the membrane integrity of microglia. And the antioxidant\u2010resveratrol 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.<\/jats:p>","DOI":"10.1002\/advs.202503389","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T08:09:43Z","timestamp":1747987783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Mechanotransduction Activates Microglia and Impairs Phagocytosis in Stiff Amyloid\u2010\u03b2 Plaques"],"prefix":"10.1002","volume":"12","author":[{"given":"Yulin","family":"Liu","sequence":"first","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an 710049 P. R. China"},{"name":"Bioinspired Engineering and Biomechanics Center (BEBC) Xi'an Jiaotong University  Xi'an 710049 P. 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