Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology & Institutes of Brain Science, Fudan University, 138 Yi-Xue-Yuan Road, Shanghai, 200032, China.
Cell Mol Neurobiol. 2019 Jul;39(5):637-650. doi: 10.1007/s10571-019-00668-6. Epub 2019 Mar 9.
Reactive microglia clustering around amyloid plaques in brain is a histopathological feature of Alzheimer's disease (AD) and reflects the contribution of neuroinflammation in AD pathogenesis. β-Amyloid peptide (Aβ) has been shown to induce a range of microglial responses including chemotaxis, cytotoxicity and inflammation, but the underlying mechanism is poorly understood. Considering the fundamental role of RhoA/ROCK signaling in cell migration and its broad implication in AD and neuroinflammation, we hypothesized that RhoA/ROCK signaling might be involved in Aβ-induced microglial responses. From in vivo mouse models including APP/PS1 transgene and fibrillar Aβ stereotactic injection, we observed the elevated expression level of RhoA in reactive microglia. Through a series in vitro cell migration, cytotoxicity and biochemistry assays, we found that RhoA/ROCK signaling plays an essential role in Aβ-induced responses of microglial BV2 cells. Small molecular agents Fasudil and Y27632 showed prominent beneficial effects, which implies the therapeutic potential of RhoA/ROCK signaling inhibitors in AD treatment.
大脑中淀粉样斑块周围反应性小胶质细胞的聚集是阿尔茨海默病（AD）的组织病理学特征，反映了神经炎症在 AD 发病机制中的贡献。β-淀粉样肽（Aβ）已被证明会引起一系列小胶质细胞反应，包括趋化性、细胞毒性和炎症，但潜在的机制尚不清楚。考虑到 RhoA/ROCK 信号在细胞迁移中的基本作用及其在 AD 和神经炎症中的广泛意义，我们假设 RhoA/ROCK 信号可能参与 Aβ 诱导的小胶质细胞反应。通过 APP/PS1 转基因和纤维状 Aβ立体定向注射等体内小鼠模型，我们观察到反应性小胶质细胞中 RhoA 的表达水平升高。通过一系列体外细胞迁移、细胞毒性和生化测定，我们发现 RhoA/ROCK 信号在 Aβ诱导的小胶质细胞 BV2 细胞反应中起着至关重要的作用。小分子药物法舒地尔和 Y27632 表现出显著的有益效果，这意味着 RhoA/ROCK 信号抑制剂在 AD 治疗中的治疗潜力。
