Cross-dataset transcriptomics-proteomics analysis identifies Tlr2, Anxa5, and Grin2a as candidate mouse-brain signatures associated with chronic cerebral hypoperfusion.

BACKGROUND

Chronic cerebral hypoperfusion (CCH) is a neurological disorder characterized by persistent insufficiency of cerebral blood flow, yet specific biomarkers and mechanistic insights are lacking.

METHODS

This study integrated transcriptomic and proteomic multi-omics analyses, along with behavioral assessments and immunofluorescence validation in a bilateral common carotid artery stenosis (BCAS) mouse model, to identify and validate candidate multi-omics biomarkers of CCH and explore their potential druggability. Leveraging public transcriptomic datasets and in-house proteomic data, differential expression analysis, protein-protein interaction network construction, and five topological algorithms identified Tlr2, Anxa5, and Grin2a as candidate biomarkers.

RESULTS

BCAS mice exhibited spatial memory impairments in behavioral tests. Immunofluorescence revealed upregulated TLR2 and ANXA5, downregulated GRIN2A, and increased TLR2-IBA1 co-localization indicating microglial activation. Tlr2 and Anxa5 positively correlated with infiltrating immune cells, whereas Grin2a showed a negative correlation. A putative ceRNA network and in silico molecular docking suggested strong binding of pirinixic acid to both TLR2 and ANXA5.

DISCUSSION: Tlr2, Anxa5, and Grin2a can serve as candidate multi-omics signature molecules of CCH in the mouse brain, with consistent alterations at the transcriptomic, proteomic, and tissue levels.