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

Aging is the predominant driver of brain proteome remodeling in wild-type and 5xFAD mice, reshaping 8,535 quantified proteins and 51 co-expression modules across lifespan.

• Why it matters: It remains unclear how much molecular change in brain proteomes reflects normal aging versus amyloid-beta (Aβ) pathology, and which pathways each selectively affects.
• What they did: The study used tandem mass tag proteomics across the lifespan in wild-type and 5xFAD mice, then integrated mouse data with human brain proteomic networks to resolve aging- and Aβ-associated molecular programs.
• The result: Aging independently alters RNA metabolism, protein translation, and neuronal pathways, while Aβ selectively suppresses mitochondrial ATP biosynthetic machinery and amplifies astrocytic and microglial activation states, with signatures conserved in human AD brain proteomes.

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