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 <jats:p>Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron\u2010glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini\u2010brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid\u2010beta (A\u03b2)\u2010overexpressing neurons and reactive astrocytes produce interferon\u2010gamma (IFN\u03b3) and excessive oxidative stress. IFN\u03b3 results in the downregulation of mitogen\u2010activated protein kinase (MAPK) and the upregulation of Kelch\u2010like ECH\u2010associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid\u20102\u2010related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NF\u03baB)\u2010axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated\u2010tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFN\u03b3\u2010driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.<\/jats:p>","DOI":"10.1002\/advs.202304357","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T07:32:15Z","timestamp":1710401535000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Neurotoxic Microglial Activation via IFN\u03b3\u2010Induced Nrf2 Reduction Exacerbating Alzheimer's Disease"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6847-3002","authenticated-orcid":false,"given":"You Jung","family":"Kang","sequence":"first","affiliation":[{"name":"Institute of Quantum Biophysics Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Department of Biophysics Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Jae","family":"Hyeon","sequence":"additional","affiliation":[{"name":"Center for Brain Disorders Brain Science Institute Korea Institute of Science and Technology  Seoul 02792 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"McQuade","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases University of California  San Francisco CA 94158 USA"},{"name":"Department of Neurobiology &amp; Behavior University of California Irvine  Irvine CA 92697 USA"},{"name":"Sue and Bill Gross Stem Cell Research Center University of California Irvine  Irvine CA 92697 USA"},{"name":"Institute for Memory Impairments and Neurological Disorders University of California Irvine  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwoon","family":"Lim","sequence":"additional","affiliation":[{"name":"IBS School University of Science and Technology (UST)  Daejeon 34114 Republic of Korea"},{"name":"Center for Cognition and Sociality Institute for Basic Science (IBS)  Daejeon 34126 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hyun","family":"Baek","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen N.","family":"Diep","sequence":"additional","affiliation":[{"name":"Institute of Quantum Biophysics Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Department of Biophysics Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh V.","family":"Do","sequence":"additional","affiliation":[{"name":"Institute of Quantum Biophysics Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeji","family":"Jeon","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Gyu","family":"Jo","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Biomedical Institute for Convergence Sungkyunkwan University  Suwon Gyeonggi 16419 Republic of Korea"},{"name":"Samsung Advanced Institute for Health Sciences and Technology Sungkyunkwan University  Seoul 16419 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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