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.

阿尔茨海默病 (AD) 的病理学以细胞外淀粉样蛋白-β (Aβ) 斑块为特征，其对周围脑组织机械特性的影响尚不清楚。小胶质细胞感知并整合微环境的生化信号。然而，小胶质细胞机械传感通路是否影响 AD 发病机制尚不清楚。在这里，我们调查了 Aβ 斑块相关组织的硬度升高，并观察了 Aβ 斑块相关小胶质细胞中机械敏感离子通道 Piezo1 的选择性上调。Piezo1 感知 Aβ 原纤维的硬度刺激，随后诱导 Ca ²⁺流入小胶质细胞聚集、吞噬作用和 Aβ 斑块压实。缺乏Piezo1 的小胶质细胞导致 Aβ 病理恶化和认知能力下降，而小胶质细胞 Piezo1 的药理学激活改善了 5×FAD 小鼠的大脑 Aβ 负荷和认知障碍。总之，我们的结果表明 Piezo1 是小胶质细胞中 Aβ 原纤维硬度的机械传感器，代表了 AD 的潜在治疗靶点。