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

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.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Neurotoxic Microglial Activation via IFNγ‐Induced Nrf2 Reduction Exacerbating Alzheimer's Disease ; day:14 ; month:03 ; year:2024 ; extent:13 ; Advanced science ; (14.03.2024) (gesamt 13)

Contributors, Places and Time

• Creator: Kang, You Jung ; Hyeon, Seung Jae ; McQuade, Amanda ; Lim, Jiwoon ; Baek, Seung Hyun ; Diep, Yen N. ; Do, Khanh V. ; Jeon, Yeji ; Jo, Dong‐Gyu ; Lee, C. Justin ; Blurton‐Jones, Mathew ; Ryu, Hoon ; Cho, Hansang

Further information

• DOI: 10.1002/advs.202304357
• URN: urn:nbn:de:101:1-2024031413411917088375
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 14.08.2025, 10:48 AM CEST