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[210716] 저널발표 Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading

김행준 │ 2021-07-14

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https://www.pnas.org/content/118/27/e2023418118


Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading

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  1. Edited by Ana Maria Cuervo, Albert Einstein College of Medicine, Bronx, NY, and approved May 26, 2021 (received for review November 16, 2020)

Significance

Neurofibrillary tangles composed of misfolded and aggregated tau protein are degraded by the autophagy–lysosomal pathway. Microglia play a central role in immune surveillance and neuroinflammation. Here, we reveal that microglial autophagy critically controls microglial metabolic and immune status and also modulates neuronal tau pathology. Autophagy deficiency induces lipid droplet formation and heightened immune response, and these phenotypes can be rescued by activating the lipid efflux system, thus establishing a mechanistic link between lipid accumulation and neuroinflammation. The development of neurofibrillary tangles closely correlates with dementia in Alzheimer’s disease, and our studies provide support that autophagy augmentation may provide therapeutic benefit through targeting both immune cell function and tau pathology.

Abstract

The autophagy–lysosomal pathway plays a critical role in intracellular clearance and metabolic homeostasis. While neuronal autophagy is known to participate in the degradation of neurofibrillary tangles composed of hyperphosphorylated and misfolded tau protein in Alzheimer’s disease and other tauopathies, how microglial-specific autophagy regulates microglial intrinsic properties and neuronal tau pathology is not well understood. We report here that Atg7, a key mediator of autophagosome biogenesis, plays an essential role in the regulation of microglial lipid metabolism and neuroinflammation. Microglia-specific deletion of Atg7 leads to the transition of microglia to a proinflammatory status in vivo and to inflammasome activation in vitro. Activation of ApoE and lipid efflux attenuates the lipid droplets accumulation and inhibits cytokine production in microglial cells with Atg7 deficiency. Functionally, we show that the absence of microglial Atg7 enhances intraneuronal tau pathology and its spreading. Our results reveal an essential role for microglial autophagy in regulating lipid homeostasis, neuroinflammation, and tau pathology.




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