Enhanced defense against mitochondrial hydrogen peroxide attenuates age-associated cognition decline

Increased mitochondrial hydrogen peroxide (H₂O₂) is associated with Alzheimer's disease and brain aging. Peroxiredoxin 3 (Prdx3) is the key mitochondrial antioxidant defense enzyme in detoxifying H₂O₂. To investigate the importance of mitochondrial H₂O₂ in age-associated cognitive decline, we compared cognition between aged (17-19months) APP transgenic mice and APP/Prdx3 double transgenic mice (dTG) and between old (24months) wild-type mice and Prdx3 transgenic mice (TG). Compared with aged APP mice, aged dTG mice showed improved cognition that was correlated with reduced brain amyloid beta levels and decreased amyloid beta production. Old TG mice also showed significantly increased cognitive ability compared with old wild-type mice. Both aged dTG mice and old TG mice had reduced mitochondrial oxidative stress and increased mitochondrial function. Moreover, CREB signaling, a signaling pathway important for cognition was enhanced in both aged dTG mice and old TG mice. Thus, our results indicate that mitochondrial H₂O₂ is a key culprit of age-associated cognitive impairment, and that a reduction of mitochondrial H₂O₂ could improve cognition by maintaining mitochondrial health and enhancing CREB signaling.