Microglial cellular stress response and type-I interferon axis aggravate neurotoxic amyloid-beta pathology in a mouse model of Alzheimer’s disease 3402

Abstract Description Neuroinflammation is recognized as a critical driver of neurodegeneration in Alzheimer’s disease (AD). We previously demonstrated that a deficiency in nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a key regulator of cellular stress responses, intensifies immune priming of microglia (MG). Here, we show that Nrf2 knockdown in human microglial-like cells upregulates type I interferon (IFN-I) effector genes. In contrast, pharmacological activation of Nrf2 suppresses interferon regulatory factor 7 expression in LPS-stimulated MG, highlighting an interaction between Nrf2 and IFN-I pathways. To investigate the role of the Nrf2/IFN-I axis in Aβ pathology, we crossbred Nrf2-/- mice with 5xFAD mice. At six months, Nrf2-/-:5xFAD mice exhibited more diffuse Thioflavin S (ThioS)-labeled fibrillar Aβ plaques. Iba1+ MG in these mice showed reduced interaction with ThioS+ Aβ, indicating impaired Aβ processing. Methoxy-X04 labeling revealed that only 10% of MG in Nrf2-/-:5xFAD mice internalized Aβ compared to 28% in Nrf2+/+:5xFAD controls, correlating with increased neuritic dystrophy and synaptic toxicity. Single-cell RNA sequencing analysis identified increased Ccl5 and Cxcl10 expression in IFN-response MG subsets, disrupted MG transition to disease-associated microglia (DAM), and impacted cytoskeletal and adhesion pathways. These findings reveal the critical role of Nrf2-IFN-I interactions in MG dysfunction and Aβ pathology, offering insights into neuroinflammatory mechanisms in AD. Funding Sources Supported by Alzheimer’s Association 24AARG-1188410 Topic Categories Neuroimmunology (NEUR)