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/p21^Cip1, 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.

功能失调的自噬与阿尔茨海默病（AD）的发病机制有关。先前的证据表明受影响神经元中自噬-溶酶体途径的多个阶段受到破坏。然而，小胶质细胞（一种与 AD 具有重要联系的细胞类型）中的自噬失调是否以及如何导致 AD 进展仍然难以捉摸。在这里，我们报道了小胶质细胞中的自噬被激活，特别是 AD 小鼠模型中淀粉样蛋白斑周围的疾病相关小胶质细胞。抑制小胶质细胞自噬会导致小胶质细胞从淀粉样斑块中脱离，抑制与疾病相关的小胶质细胞，并加重 AD 小鼠的神经病理学。从机制上讲，自噬缺陷会促进衰老相关的小胶质细胞，表现为增殖减少、 Cdkn1a /p21 ^Cip1增加、营养不良的形态和衰老相关的分泌表型。药物治疗可去除 AD 小鼠中自噬缺陷的衰老小胶质细胞并减轻神经病理学。我们的研究证明了小胶质细胞自噬在调节淀粉样斑块的稳态和预防衰老方面的保护作用；去除衰老的小胶质细胞是一种有前途的治疗策略。