Innate immune signaling by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease

Z-DNA is a non-canonical structure capable of activating innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated detection of Z-DNA in Alzheimer's disease (AD) remains poorly defined. Here, we found that ZBP1 is amplified in AD microglia, triggering innate immune response and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that fragmented oxidized mtDNA (Ox-mtDNA), produced during oxidative stress, cleaved by mitochondria nucleases, and released via the mPTP-VDAC channel, serves as the source of Z-form mtDNA. We demonstrated that Z-DNA-activated ZBP1 engages RIPK1, promoting RIPK1 kinase activation and RIPK1-kinase dependent transcription of pro-inflammatory molecules and intracellular inflammatory signaling mediators for various inflammatory pathways. Deletion of ZBP1 or genetic inhibition of RIPK1 kinase limits the innate immune response, neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings demonstrate that innate immune signaling by Z-form mtDNA-ZBP1-RIPK1 axis drives microglia-mediated neuroinflammation in AD, providing new insights into the immune mechanisms underlying AD pathogenesis and revealing a potential therapeutic avenue for AD. mRNA profiles of hippocampus derived from paired WT, 5×FAD, Ripk1D138N/D138N, Zbp1-/-, and Zbp1-/-;5×FAD mice aged 9 months. ZBP1-binding RNA profiles of hippocampus derived from paired WT and 5×FAD.