Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Choi et al. show that autophagy is activated in disease-associated microglia in Alzheimer's disease mouse models, which prevents microglial senescence entry. Blocking microglial autophagy aggravates neuropathology in Alzheimer's disease mice. 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.

Automated summary

Choi et al. demonstrate that autophagy is activated in microglia, particularly in disease-associated microglia surrounding amyloid plaques in Alzheimer's disease mouse models. Blocking microglial autophagy worsens neuropathology in AD mice. Dysfunction in autophagy has been implicated in the pathogenesis of AD, and previous studies have shown disruptions in autophagy-lysosomal pathway in affected neurons. However, the role of deregulated autophagy in microglia, a cell type associated with AD, and its contribution to disease progression, remained unclear.