Neurotoxic Microglial Activation via IFNγ‐Induced Nrf2 Reduction Exacerbating Alzheimer's Disease

Autor: You Jung Kang, Seung Jae Hyeon, Amanda McQuade, Jiwoon Lim, Seung Hyun Baek, Yen N. Diep, Khanh V. Do, Yeji Jeon, Dong‐Gyu Jo, C. Justin Lee, Mathew Blurton‐Jones, Hoon Ryu, Hansang Cho
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Advanced Science, Vol 11, Iss 20, Pp n/a-n/a (2024)
Druh dokumentu: article
ISSN: 2198-3844
20230435
DOI: 10.1002/advs.202304357
Popis: 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.
Databáze: Directory of Open Access Journals
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