Proteomic Characterization of the Dynamics of Ischemic Stroke in Mice

Novel therapies and biomarkers are needed for the treatment of acute ischemic stroke (AIS). This study aimed to provide comprehensive insights into the dynamic proteome changes and underlying molecular mechanisms post-ischemic stroke. TMT-coupled proteomic analysis was conducted on mouse brain cortex tissue from five time points up to 4 weeks poststroke in the distal hypoxic-middle cerebral artery occlusion (DH-MCAO) model. We found that nearly half of the detected proteome was altered following stroke, but only similar to 8.6% of the changes were at relatively large scales. Clustering on the changed proteome defined four distinct expression patterns characterized by temporal and quantitative changes in innate and adaptive immune response pathways and cytoskeletal and neuronal remodeling. Further analysis on a subset of 309 top hits, which temporally responded to stroke with relatively large and sustained changes, revealed that they were mostly secreted proteins, highly correlated to different cortical cytokines, and thereby potential pharmacodynamic biomarker candidates for inflammation-targeting therapies. Closer examination of the top enriched neurophysiologic pathways identified 57 proteins potentially associated with poststroke recovery. Altogether, our study generated a rich dataset with candidate proteins worthy of further validation as biomarkers and/or therapeutic targets for stroke. The proteomics data are available in the PRIDE Archive with identifier PXD025077.

Automated summary

This study utilized proteomic analysis to investigate the dynamic changes in protein expression post-ischemic stroke, identifying potential biomarkers and therapeutic targets associated with immune response, neuronal remodeling, and inflammation-targeting therapies. A subset of proteins showed large and sustained changes post-stroke, indicating their potential as pharmacodynamic biomarker candidates. Additionally, neurophysiologic pathways associated with poststroke recovery were also identified, providing valuable insights for future research and therapy development.