Network analysis of mouse brain proteomes resolves molecular and cellular endophenotypes of aging and Aβ pathology

Aging and Alzheimer's disease (AD) impact the brain in both shared and unique ways, though their relative roles in molecular changes remain unclear. In this study, researchers conducted tandem mass tag proteomics across the lifespan in wild-type and genetically modified 5xFAD mice, then combined these findings with human brain proteomic networks to identify key aging and amyloid-beta (Aβ)-associated molecular programs.

The analysis of nearly 8,500 proteins revealed 51 co-expression modules encompassing neuronal, mitochondrial, glial, vascular, and proteostatic pathways. Aging was found to be the main driver of proteomic remodeling, causing widespread alterations in RNA metabolism, protein translation, and neuronal pathways, regardless of Aβ presence.

Meanwhile, Aβ pathology selectively altered a smaller set of age-dependent processes, such as diminishing mitochondrial ATP biosynthetic machinery and intensifying astrocytic and microglial activation states. These critical aging and disease-linked molecular signatures were also detected in human AD brain proteomes. The findings demonstrate that aging primarily dictates brain proteome organization while pinpointing specific mechanisms through which Aβ pathology reshapes age-associated biological processes.

Moreover, these results underscore molecular mechanisms of human aging and AD pathology that can be replicated in mouse models.