Brain-derived exosomes from aged mice accelerate cognitive decline in repeated mild traumatic brain injury by activating neuronal Tnfrsf25.

Aging increases vulnerability to cognitive decline after repetitive mild traumatic brain injury (rm-TBI), yet mechanisms linking age-related factors to neurodegeneration remain poorly understood. This study investigated how brain-derived exosomes from aged mice (A-Exo) worsen rm-TBI outcomes. In a murine rm-TBI model, intranasal A-Exo administration significantly exacerbated spatial memory deficits and hippocampal neuronal apoptosis compared to brain-derived exosomes from young mice (Y-Exo) or controls. Proteomic analysis revealed the enrichment of Tnfrsf21 in brain-derived exosomes from aged mice, and these exosomes were closely associated with the neuronal death pathway. Our further investigations demonstrated that A-Exo could upregulate the expression of tumor necrosis factor receptor superfamily member 25 (Tnfrsf25) in neurons. Knockdown of Tnfrsf25 reversed A-Exo-induced apoptosis, confirming its mechanistic role. Molecular docking identified desoxycortone and propantheline as potent Tnfrsf25 inhibitors, which rescued neuronal viability in A-Exo treated cells. These findings establish aged exosomes as active contributors to post-TBI neurodegeneration and implicate Tnfrsf25 as a key mediator of neuronal damage. The discovery of repurposed drugs targeting Tnfrsf25 provides a novel therapeutic strategy for age-exacerbated neurotrauma. This study bridges critical gaps in understanding rm-TBI-related cognitive decline by elucidating age-dependent exosomal mechanisms and identifying actionable molecular targets.