Autophagy restricts senescence and enables microglia to engage amyloid plagues in neuroprotection

Microglia are essential to maintain brain homeostasis, but when dysregulated, exert pathogenic functions in Alzheimer's disease (AD). Recent evidence has implicated senescent/dystrophic microglia in the pathological process of AD. Whether microglial senescence is a cause or consequence of AD pathogenesis however is unclear. Here we report that autophagy, a lysosomal degradation pathway, restricts cellular senescence of microglia and confer neuroprotection in AD mouse model. Autophagy-deficient microglia show hallmarks of cellular senescence evidenced by reduced proliferation, increased Cdkn1a/p21Cip, dystrophy, and typical secretory phenotype. While disease-associated microglia (DAM) surrounding amyloid plaques exhibit heightened autophagy, autophagy deficient, senescent microglia (SAM) disengage from and thus fail to limit the diffusive amyloid plaques, causing enhanced tau phosphorylation and neurotoxicity in AD model. Treatment of senolytic drugs removes senescent microglia and alleviates neuropathology. Our study demonstrates a causal role of autophagy impairment in microglial senescence and neurotoxicity and suggests therapeutic potential of senolytic treatment for AD. Overall design: FACS-sorted microglia from 8-month-old mice (ATG7FF and ATG7FF;Cx3cr1CreER, at 6-months post tamoxifen injection) were subject to single-cell RNA sequencing. Microglia were pooled from 3 forebrains of ATG7FF or 4 forebrains of ATG7FF;Cx3cr1CreER. Forebrains from 8-months-old mice (ATG7FF;5xFAD, and ATG7FF;Cx3cr1CreER;5xFAD, at 6-months post tamoxifen injection) were subject to a bulk RNA RNA sequencing.