Ni Junjun, Xie Zhen, Quan Zhenzhen, Meng Jie, Qing Hong
Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China.
Department of Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Glia. 2024 Feb;72(2):227-244. doi: 10.1002/glia.24465. Epub 2023 Aug 31.
Microglia are the resident phagocytes of the brain, where they primarily function in the clearance of dead cells and the removal of un- or misfolded proteins. The impaired activity of receptors or proteins involved in phagocytosis can result in enhanced inflammation and neurodegeneration. RNA-seq and genome-wide association studies have linked multiple phagocytosis-related genes to neurodegenerative diseases, while the knockout of such genes has been demonstrated to exert protective effects against neurodegeneration in animal models. The failure of microglial phagocytosis influences AD-linked pathologies, including amyloid β accumulation, tau propagation, neuroinflammation, and infection. However, a precise understanding of microglia-mediated phagocytosis in Alzheimer's disease (AD) is still lacking. In this review, we summarize current knowledge of the molecular mechanisms involved in microglial phagocytosis in AD across a wide range of pre-clinical, post-mortem, ex vivo, and clinical studies and review the current limitations regarding the detection of microglia phagocytosis in AD. Finally, we discuss the rationale of targeting microglial phagocytosis as a therapeutic strategy for preventing AD or slowing its progression.
小胶质细胞是大脑中的常驻吞噬细胞，它们主要负责清除死亡细胞以及去除未折叠或错误折叠的蛋白质。参与吞噬作用的受体或蛋白质活性受损会导致炎症加剧和神经退行性变。RNA测序和全基因组关联研究已将多个与吞噬作用相关的基因与神经退行性疾病联系起来，而在动物模型中，敲除此类基因已被证明对神经退行性变具有保护作用。小胶质细胞吞噬功能的失效会影响与阿尔茨海默病（AD）相关的病理过程，包括淀粉样β蛋白的积累、tau蛋白的传播、神经炎症和感染。然而，目前仍缺乏对阿尔茨海默病（AD）中小胶质细胞介导的吞噬作用的精确理解。在这篇综述中，我们总结了广泛的临床前、尸检、体外和临床研究中关于AD中小胶质细胞吞噬作用所涉及分子机制的现有知识，并回顾了目前在检测AD中小胶质细胞吞噬作用方面存在的局限性。最后，我们讨论了将小胶质细胞吞噬作用作为预防AD或减缓其进展的治疗策略的基本原理。
