Aging-Associated Nrf2 Loss in Microglia Exacerbates Neuroinflammation and Trained Immunity 2249338

Abstract Introduction Aging is the greatest risk factor for Alzheimer’s disease (AD) and related dementias, with chronic neuroinflammation playing a central role in disease progression. Microglia–the brain’s resident immune cells–undergo age-related changes that exacerbate neuroimmune dysfunction. The transcription factor Nuclear Factor Erythroid 2—Related Factor 2 (Nrf2), a key regulator of cellular stress responses, has an unclear role in microglial aging. Methods To investigate the role of Nrf2 in aging, we employed both Nrf2-deficient (Nrf2⁻/⁻) mice and microglia-specific Nrf2 knockout (MG-Nrf2-KO) models. Immune profiles and cognitive functions were assessed using flow cytometry and behavioral testing, respectively. Results Our results show that Nrf2 expression declines in aged microglia, coinciding with increased neuroinflammation. Nrf2⁻/⁻ mice exhibit heightened microglial activation, elevated MHC class II expression, and infiltration of peripheral immune cells, including CD4+ T cells. Flow cytometry confirms that these infiltrating cells localize within the brain parenchyma rather than remaining in circulation. Moreover, Nrf2⁻/⁻ microglia adopt a disease-associated microglia (DAM)-like phenotype, marked by upregulation of activation markers and altered gene expression profiles. Loss of Nrf2 impairs motor learning and leads to cognitive deficits in aging mice. Mechanistically, Nrf2-deficient microglia display enhanced trained immunity, characterized by exaggerated inflammatory responses to systemic immune challenges. In MG-Nrf2-KO mice, repeated lipopolysaccharide (LPS) exposure results in elevated IL-1β production, indicating that Nrf2 modulates microglial immune memory. Conclusion These findings suggest that targeting Nrf2 signaling may offer a promising therapeutic strategy to reduce microglial hyperactivation, chronic neuroinflammation, and cognitive decline associated with aging and neurodegenerative diseases. Funding Source NIH R21AG070971, NIH R01NS102449 Topic Categories Neuroimmunology (NEUR)