Proteomic Analysis of Adult Human Hippocampal Subfields Demonstrates Regional Heterogeneity in the Protein Expression

Abstract

Background: Distinct hippocampal subfields are known to get affected during aging, psychiatric disorders, and various neurological and neurodegenerative conditions. To understand the biological processes associated with each subfield, it is important to understand its heterogeneity at the molecular level. To address this lacuna, we investigated the proteomic analysis of hippocampal subfieldsthe cornu ammonis sectors (CA1, CA2, CA3, CA4) and dentate gyrus (DG) from healthy adult human cohorts. Findings: Microdissection of hippocampal subfields from archived formalin-fixed paraffin-embedded tissue sections followed by TMT-based multiplexed proteomic analysis resulted in the identification of 5,593 proteins. Out of these, 890 proteins were found to be differentially abundant among the subfields. Further bioinformatics analysis suggested proteins related to gene splicing, transportation, myelination, structural activity, and learning processes to be differentially abundant in DG, CA4, CA3, CA2, and CA1, respectively. A subset of proteins was selected for immunohistochemistry-based validation in an independent set of hippocampal samples. Conclusions: We believe that our findings will effectively pave the way for further analysis of the hippocampal subdivisions and provide awareness of its subfield-specific association to various neurofunctional anomalies in the future. The current mass spectrometry data is deposited and publicly made available through ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD029697.

Mapping the spatial proteomic signature of dorsal and ventral hippocampus in a mouse model of early Alzheimer’s disease: changes in synaptic plasticity-related proteins associated with sexual dimorphism

“…A recent proteomic analysis has demonstrated a regional heterogeneity in the protein expression of the different hippocampal subfields (i.e. CA1, CA2, CA3 and dentate gyrus) in healthy humans [101], and regarding AD, lipids expression seem to change specifically in the CA1 subfield of the hippocampus [102]. Since each subfield is attributed a different function [103][104][105][106], the question arises whether similar results to those presented here would be observed regarding synaptic plasticity-related proteins if the hippocampal proteome of each subfield is analyzed independently.…”

Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

“…However, CA3 and CA1 subserve specific, yet complementary functions, such as the encoding of memory acquisition, consolidation, and retrieval [27,28]. Indeed, the microdissection of both human and rodent hippocampal subfields contains differentially abundant proteins and responds selectively to modification of local cues in the environment as well as to ischemic and hypoxic conditions and neurodegeneration [29][30][31].…”