Age-Associated Molecular Changes in Human Hippocampus Subfields as Determined by Quantitative Proteomics

The hippocampus demonstrates age-associated changes in functions, neuronal circuitry, and plasticity during various developmental stages. On the contrary, there is a significant knowledge gap on age-associated proteomic alterations in the hippocampus subfields. Using tandem mass tag-based high-resolution mass spectrometry and quantitative proteomics, we report here age-associated changes in the human hippocampus at the subregional level. We used formalin-fixed paraffin-embedded hippocampal tissue sections from a total of 12 healthy individuals, with 3 individuals from each of the 4 different age groups, specifically, 1-10, 21-30, 31-40, and 81-90 years. We found that lysosome and oxidative phosphorylation were the pathways enriched in the 81- to 90-year age group. On the contrray, nervous system development, synaptic plasticity and transmission, messenger RNA (mRNA) splicing, and electron transport chain (ETC) complex-I activity were the enriched biological processes observed in the younger age groups. In a hippocampus subfield context, our topline findings on age-associated proteome changes include altered expression of proteins associated with adult neurogenesis with age in the dentate gyrus and increased expression of immune response-associated proteins with age in certain cornu ammonis sectors of the hippocampus. Signal peptide analysis predicted hippocampal proteins with secretory potential. While these new findings warrant replication in larger study samples, the current data contribute to (1) our understanding of the molecular basis of proteomic changes across various age groups in hippocampus subfields in healthy individuals, and (2) the design and interpretation of future research on the age-associated neurodegenerative disorders.