期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2023418118
关键词
Alzheimer's disease; autophagy; lipid metabolism; microglia; tau
资金
- NIH [R01 NS093652, R01 AG020670, R01 AG057509, RF1 AG054111, RF1 AG062257]
- [NCI-CA125123]
Studies indicate that microglial-specific autophagy, represented by Atg7, plays a crucial role in regulating lipid metabolism and neuroinflammation. Deletion of Atg7 in microglia leads to a proinflammatory status and exacerbates intraneuronal tau pathology.
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 microglialspecific 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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