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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence
Insup Choi1, Minghui Wang2,3, Seungyeul Yoo4
1Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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.
Insights
Microglial autophagy protects against Alzheimer's disease by clearing amyloid plaques and preventing harmful cell senescence. Inhibiting this process worsens disease, but removing senescent cells offers a therapeutic avenue.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Dysfunctional autophagy is linked to Alzheimer's disease (AD) pathogenesis, particularly in neurons.
- The role of autophagy in microglia, crucial immune cells in AD, remains unclear.
Purpose of the Study:
- To investigate the role of microglial autophagy in Alzheimer's disease progression.
- To elucidate the mechanisms by which autophagy influences microglial function and neuropathology.
Main Methods:
- Utilized AD mouse models to study microglial autophagy.
- Inhibited microglial autophagy and observed effects on amyloid plaques and neuropathology.
- Assessed microglial senescence markers and therapeutic interventions.
Main Results:
- Autophagy is activated in microglia surrounding amyloid plaques in AD models.
- Inhibition of microglial autophagy leads to plaque disengagement, suppressed disease-associated microglia, and worsened neuropathology.
- Autophagy deficiency promotes microglial senescence, characterized by reduced proliferation and altered morphology.
Conclusions:
- Microglial autophagy plays a protective role in regulating amyloid plaque homeostasis and preventing cellular senescence in AD.
- Targeting senescent microglia represents a potential therapeutic strategy for Alzheimer's disease.
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