Abstract WP367: Conserved and Age-Specific Cortical Transcriptomic Signatures after Ischemic Stroke in Mice

Background: Ischemic stroke is a major cause of death and disability worldwide. Age impacts stroke outcomes, but the molecular mechanisms remain incompletely understood. Permanent middle cerebral artery occlusion (MCAO) in mice is a widely used model to study ischemic brain injury. This study examined gene expression changes following stroke by reanalysis of age-stratified cortical transcriptomic data. Methods: We reanalyzed bulk RNA-seq data (GSE137482) from the parietal cortex of female C57BL/6 mice aged 3 or 18 months (n=6/group) at 3 days post-MCAO or sham surgery. Reads were normalized by trimmed mean of M-values in edgeR. Differential expression was assessed by age groups using exactTest of R packages, and results compared to identify shared and unique responses. Gene Ontology enrichment was performed using the enrichGO function in clusterProfiler. Results: MCAO induced extensive transcriptional reprogramming in both age groups, with substantial overlap, where 2,145 genes were upregulated and 1,089 downregulated in both groups. Shared upregulated pathways included complement activation, chemokine signaling, immune cell recruitment, endothelial adhesion, hypoxia response, extracellular matrix remodeling, and platelet-related processes. Downregulated genes were enriched for calcium-mediated exocytosis and synaptic vesicle trafficking.: Age-specific differences were significant. In young mice, 346 genes were uniquely upregulated and 178 downregulated, with selective induction of platelet adhesion/maturation genes and downregulation of somatostatin. Aged mice exhibited a broader shift, with 1,141 upregulated and 1,685 downregulated genes. These changes indicate broad immune activation (chemokines, immune checkpoints, scavenger receptors), with additional upregulation of select extracellular matrix and coagulation genes, accompanied by marked downregulation of angiogenic (Vegfa), synaptic, and calcium channel transcripts. Conclusion: Permanent MCAO elicits both conserved and age-divergent cortical gene expression programs. Core inflammatory, endothelial, and hypoxic responses are preserved across ages. While young brains preferentially induce platelet-related pathways, aged brains display broader immune activation with extracellular matrix remodeling, accompanied by marked downregulation of pro-angiogenic (Vegfa), synaptic, and calcium signaling genes. These age-dependent patterns suggest potential molecular targets for tailored stroke therapies.