美国西奈山医学院岳振宇研究团队发现自噬使小胶质细胞参与淀粉样斑块形成，防止小胶质细胞衰老。2023年5月25日出版的《自然—细胞生物学》杂志发表了这项成果。

他们报道在阿尔茨海默病(AD)小鼠模型中，自噬在小胶质细胞中被激活，特别是在淀粉样斑块周围的疾病相关小胶质细胞中。抑制小胶质细胞自噬导致小胶质细胞脱离淀粉样斑块，抑制疾病相关的小胶质细胞，并加重AD小鼠的神经病理学。机制上，自噬缺陷促进衰老相关的小胶质细胞，如增殖减少，Cdkn1a/p21Cip1增加，营养不良形态和衰老相关的分泌表型。药物治疗可去除自噬缺陷的衰老小胶质细胞，减轻AD小鼠的神经病理。

这项研究证明了小胶质细胞自噬在调节淀粉样斑块的稳态和防止衰老方面的保护作用，清除衰老小胶质细胞是一种很有前途的治疗策略。

据悉，功能失调的自噬与AD的发病机制有关。先前的证据表明，在受影响的神经元中，自噬-溶酶体途径的多个阶段被破坏。然而，小胶质细胞中不受调节的自噬是否以及如何促进阿尔茨海默病的进展仍然未知。

附：英文原文

Title: Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Author: Choi, Insup, Wang, Minghui, Yoo, Seungyeul, Xu, Peng, Seegobin, Steven P., Li, Xianting, Han, Xian, Wang, Qian, Peng, Junmin, Zhang, Bin, Yue, Zhenyu

Issue&Volume: 2023-05-25

Abstract: Dysfunctional autophagy has been implicated in the pathogenesis of Alzheimer’s disease (AD). Previous evidence suggested disruptions of multiple stages of the autophagy-lysosomal pathway in affected neurons. However, whether and how deregulated autophagy in microglia, a cell type with an important link to AD, contributes to AD progression remains elusive. Here we report that autophagy is activated in microglia, particularly of disease-associated microglia surrounding amyloid plaques in AD mouse models. Inhibition of microglial autophagy causes disengagement of microglia from amyloid plaques, suppression of disease-associated microglia, and aggravation of neuropathology in AD mice. Mechanistically, autophagy deficiency promotes senescence-associated microglia as evidenced by reduced proliferation, increased Cdkn1a/p21Cip1, dystrophic morphologies and senescence-associated secretory phenotype. Pharmacological treatment removes autophagy-deficient senescent microglia and alleviates neuropathology in AD mice. Our study demonstrates the protective role of microglial autophagy in regulating the homeostasis of amyloid plaques and preventing senescence; removal of senescent microglia is a promising therapeutic strategy.

DOI: 10.1038/s41556-023-01158-0

Source: https://www.nature.com/articles/s41556-023-01158-0