조한상 (성균관대학교)

한빛사논문

조회258

성균관대학교

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Adv. Sci., Mar 14 2024, | https://doi.org/10.1002/advs.202304357 Neurotoxic Microglial Activation via IFNγ-Induced Nrf2 Reduction Exacerbating Alzheimer's Disease

You Jung Kang ^{1 2}, Seung Jae Hyeon ³, Amanda McQuade ^{4 5 6 7}, Jiwoon Lim ^{8 9}, Seung Hyun Baek ¹⁰, Yen N Diep ^{1 2 11}, Khanh V Do ^{1 11}, Yeji Jeon ¹⁰, Dong-Gyu Jo ^{10 12 13}, C Justin Lee ⁹, Mathew Blurton-Jones ^{5 6 7}, Hoon Ryu ³, Hansang Cho ^{1 2 11 *}

¹Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
²Department of Biophysics, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
³Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
⁴Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94158, USA.
⁵Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
⁶Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
⁷Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, 92697, USA.
⁸IBS School, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea.
⁹Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, Republic of Korea.
¹⁰School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
¹¹Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
¹²Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
¹³Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 16419, Republic of Korea.

^*Corresponding author: correspondence to Hansang Cho

Abstract

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-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aβ)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau 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 IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-20)
연구진국내(교신)+국외 연구진
분야 바이오·의료융합 > 바이오·의료융합 기타

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