Liu Yulin, Zhang Junjie, Zhao Yuxiang, Fang Feixiang, Zhang Siyu, An Qiqi, Zhuang Jian, Xu Feng, Li Fei
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.
Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, P. R. China.
Adv Sci (Weinh). 2025 Aug;12(30):e03389. doi: 10.1002/advs.202503389. Epub 2025 May 23.
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.
在阿尔茨海默病（AD）中，小胶质细胞被淀粉样β（Aβ）斑块相关微环境中的机械和生化信号激活，从而引发神经炎症。然而，Aβ硬度对小胶质细胞激活的影响以及炎症与吞噬作用之间的动态相互作用仍不清楚。在此，构建了一种体外Aβ斑块相关小胶质细胞微环境模型，并研究了Aβ斑块的硬度如何通过PIEZO1机械转导途径触发小胶质细胞激活。采用扫描电化学显微镜和扫描离子电导显微镜原位监测小胶质细胞的活性氧释放、膜通透性和吞噬活性。研究发现，Aβ硬度驱动小胶质细胞早期激活，形成氧化应激微环境，损害小胶质细胞的膜完整性。而抗氧化剂白藜芦醇可有效改善受损小胶质细胞的吞噬功能障碍。这项工作揭示了小胶质细胞中机械信号、神经炎症和吞噬功能障碍之间的复杂相互作用，并提出了针对AD中小胶质细胞功能障碍的潜在治疗策略。
