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

Abstract

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)