Zhang Guoxin, Peng Qinyu, Guo Xiaodi, Pan Lina, Xiong Min, Zhang Xingyu, Dai Lijun, Zhang Zhaohui, Xiao Tingting, He Juanfeng, Liu Miao, Ke Wei, Zhang Zhentao
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Aging Cell. 2025 Feb;24(2):e14396. doi: 10.1111/acel.14396. Epub 2024 Nov 1.
The accumulation of amyloid-β (Aβ) and overactivation of microglia contribute to the pathogenesis of Alzheimer's disease (AD), but the interaction between microglial activation and Aβ deposition in AD remains elusive. Here we revealed that Aβ activates microglia and promotes the release of Galectin-9 (Gal-9), a member of the β-galactoside-binding family of lectins. The levels of Gal-9 in the cerebrospinal fluid and brain tissues of AD patients are higher than those in control subjects. Gal-9 interacts with Aβ and promotes its aggregation, generating Gal-9-Aβ fibrils with enhanced seeding activity and neurotoxicity. The expression of Gal-9 increases with age in the brains of APP/PS1 transgenic mice. Knockout of Gal-9 in APP/PS1 mice substantially reduced Aβ sedimentation, neuroinflammation, and cognitive impairment. Moreover, depletion of Gal-9 inhibited the seeding activity of brain homogenates from APP/PS1 mice. These findings reveal a mechanism by which microglia-derived Gal-9 accelerates Aβ aggregation and seeding in AD. Thus, strategies aimed at inhibiting Gal-9 may hold promise as a disease-modifying therapy to alleviate AD pathology.
淀粉样β蛋白（Aβ）的积累和小胶质细胞的过度激活是阿尔茨海默病（AD）发病机制的重要因素，但AD中小胶质细胞激活与Aβ沉积之间的相互作用仍不清楚。在此，我们发现Aβ激活小胶质细胞并促进半乳糖凝集素-9（Gal-9）的释放，Gal-9是β-半乳糖苷结合凝集素家族的成员。AD患者脑脊液和脑组织中Gal-9的水平高于对照组。Gal-9与Aβ相互作用并促进其聚集，产生具有增强播种活性和神经毒性的Gal-9-Aβ纤维。在APP/PS1转基因小鼠的大脑中，Gal-9的表达随年龄增加。在APP/PS1小鼠中敲除Gal-9可显著减少Aβ沉积、神经炎症和认知障碍。此外，Gal-9的缺失抑制了APP/PS1小鼠脑匀浆的播种活性。这些发现揭示了一种机制，即小胶质细胞来源的Gal-9加速AD中Aβ的聚集和播种。因此，旨在抑制Gal-9的策略有望成为一种改善疾病的疗法，以减轻AD病理。
