title: Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome.
abstract: Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that Aβ interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Cho
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hoe-Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Jeon
authors.affiliation: Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea; Department of Medicine; Graduate School; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hun-Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Department of Medicine; Graduate School; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hyung-Joon
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Department of Medicine; Graduate School; University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Hong-Mi
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Alzheimer Disease Experts Lab (ADEL); Asan Institute of Life Sciences; Asan Medical Center; University of Ulsan College of Medicine; Seoul, Korea; Department of Anatomy and Cell Biology; University of Ulsan College of Medicine; Seoul, Korea; Bio-Medical Institute of Technology (BMIT); University of Ulsan College of Medicine; Seoul, Korea; Cell Dysfunction Research Center (CDRC); University of Ulsan College of Medicine; Seoul, Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D005110:Extracellular Space / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009474:Neurons / Q000473:pathology; D059748:Proteolysis; D000071456:Sequestosome-1 Protein; D035582:Transcription Factor TFIIIA / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C502661:Atg7 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005136:Eye Proteins; D006360:Heat-Shock Proteins; D058847:Inflammasomes; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C409460:OPTN protein, human; C501288:Optn protein, mouse; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D035582:Transcription Factor TFIIIA; D055372:AMP-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; D000071193:Autophagy-Related Protein 7
keywords: Alzheimer disease; NLRP3; autophagy; microglia; β-amyloid