최인섭 (Icahn School of Medicine at Mount Sinai) | 한빛사논문 > 한빛사

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Icahn School of Medicine at Mount Sinai

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Nat. Cell Biol., 2023 May 25 | https://doi.org/10.1038/s41556-023-01158-0 Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Insup Choi¹, Minghui Wang^2,3, Seungyeul Yoo⁴, Peng Xu^2,3, Steven P. Seegobin¹, Xianting Li¹, Xian Han^5,6, Qian Wang^2,3, Junmin Peng ⁵, Bin Zhang^2,3,7& Zhenyu Yue¹

¹Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴Sema4, Stamford, CT, USA.
⁵Departments of Structural Biology and Developmental Neurobiology, Saint Jude Children’s Research Hospital, Memphis, TN, USA.
⁶Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.
⁷Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Corresponding author : Correspondence to Zhenyu Yue.

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/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.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-06-26)
연구진국외 연구진
분야 의약학 > 신경의학

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