Impact of IL-21 on Neuroinflammation and Brain Aging 4409

Abstract Description Immunosenescence—the aging of the immune system—has been implicated in driving neuroinflammation and exacerbating neuronal dysfunction in age-related neurological diseases like AD. Despite this progress, the specific immune processes that link aging to AD progression remain poorly understood. Our recent findings identify the pro-inflammatory cytokine interleukin-21 (IL-21) as a critical player in AD. Elevated IL-21 levels were detected in the circulation of individuals with AD. Correspondingly, L-21R expression was increased in the hippocampi of both human AD patients and 5xFAD mice, a model of accelerated AD. Peripheral IL-21 injections in 5xFAD mice enhanced AD pathogenesis. Furthermore, we found that IL-21 levels increase with age, even in healthy individuals, with significantly higher circulating IL-21 levels in aged subjects compared to younger individuals. Aged human and mouse hippocampi also exhibited increased IL-21R expression. Importantly, intravenous IL-21 administration in healthy young mice induced neuroinflammation, activated microglia and astrocytes, and promoted lipid droplet accumulation in microglia—hallmarks of dysfunctional immune response and neuronal injury. Collectively, our findings highlight IL-21 as a potential link between aging, immune dysfunction, and AD, underscoring its role as a promising target for therapeutic interventions in age-related neurodegenerative diseases. Funding Sources N/A Topic Categories Neuroimmunology (NEUR)