Synaptic mitochondrial oxidative stress drives individual variability in age-related cognitive decline in mice

Abstract

Aging leads to cognitive decline with considerable individual variability, yet the biological mechanisms remain unclear. Here we performed ultrastructural and proteomic analyses of the medial prefrontal cortex (mPFC) alongside behavioral assessments of attentional set shifting in mice across age groups. Although reduced synaptic density did not consistently lead to cognitive decline, proteomic analyses of synaptosomes and whole tissue revealed that the molecular signatures associated with individual variability in cognitive decline were distinct from those associated with chronological aging, and that synaptic mitochondria and their proteins were more abundant in aged mice with greater cognitive decline. Moreover, treatment with the mitochondria-targeted antioxidant MitoQ reduced the abundance of synaptic mitochondrial proteins, including pro-apoptotic proteins, and mitigated age-related cognitive decline. These findings demonstrate that synaptic mitochondrial oxidative stress in the mPFC, distinct from chronological age-related processes, contributes to individual variability in age-related cognitive decline and offers a potential target for prevention and intervention.