2. Academic Validation
  3. Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease

Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease

  • Immunity. 2025 Aug 25:S1074-7613(25)00333-4. doi: 10.1016/j.immuni.2025.07.024.
Ziwen Song 1,  Xingxing Xie 2,  Yulu Chen 2,  Boxin Zhang 3,  Xingyan Li 2,  Yuanxin Yang 2,  Wei Mo 4,  Jian Zhang 5,  Daichao Xu 6
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 101408, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 3 Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China.
  • 4 Liangzhu Laboratory, Zhejiang University, Hangzhou 310012, China. Electronic address: weimo@zju.edu.cn.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou 215031, China. Electronic address: zhangjian1002@suda.edu.cn.
  • 6 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China; Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai 200031, China. Electronic address: xudaichao@sioc.ac.cn.
PMID: 40902587 DOI: 10.1016/j.immuni.2025.07.024
Abstract

Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by Amyloid-β (Aβ)-induced oxidative stress, was fragmented and released into the cytoplasm, forming Z-DNA. Z-DNA-activated ZBP1 engaged receptor-interacting protein kinase 1 (RIPK1), promoting its kinase activation and inducing transcription of pro-inflammatory molecules and inflammatory signaling mediators. Genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings reveal that oxidation induces the Z conformer in mtDNA and establish the ZBP1-RIPK1 axis as a key driver of AD neuroinflammation, providing insights into the immune mechanisms underlying AD pathogenesis and identifying a potential therapeutic target.

Keywords

8-oxoguanine; Alzheimer's disease; DNA fragmentation; RIPK1; Z-DNA; ZBP1; amyloid-β; mitochondrial DNA; neuroinflammation; oxidative stress.

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