Proteomic Characterization of the Dynamics of Ischemic Stroke in Mice
Rong-Fang Gu1, Terry Fang2, Ashley Nelson2
1Chemical Biology and Proteomics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Abstract:
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 ∼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.
Insights
This study reveals dynamic proteome changes after acute ischemic stroke (AIS), identifying potential protein biomarkers for inflammation and recovery. These findings offer new targets for stroke therapies.
Area of Science:
- Neuroscience
- Proteomics
- Biochemistry
Background:
- Acute ischemic stroke (AIS) necessitates novel therapeutic strategies and reliable biomarkers.
- Understanding the dynamic molecular changes post-stroke is crucial for developing effective treatments.
Purpose of the Study:
- To comprehensively analyze proteome alterations and molecular mechanisms in the brain following ischemic stroke.
- To identify potential protein biomarkers and therapeutic targets for AIS.
Main Methods:
- Utilized TMT-coupled proteomic analysis on mouse brain cortex tissue.
- Employed the distal hypoxic-middle cerebral artery occlusion (DH-MCAO) model at five time points up to 4 weeks post-stroke.
- Performed clustering analysis to identify distinct proteome expression patterns.
Main Results:
- Nearly half of the detected proteome showed alterations post-stroke, with approximately 8.6% exhibiting significant changes.
- Identified four distinct proteome expression patterns linked to immune responses and neuronal remodeling.
- Discovered 309 "top hit" proteins, predominantly secreted, correlated with cytokines, suggesting potential pharmacodynamic biomarker candidates for inflammation-targeting therapies.
- Identified 57 proteins potentially involved in post-stroke recovery pathways.
Conclusions:
- Generated a valuable dataset of dynamic proteome changes following ischemic stroke.
- Highlighted candidate proteins for validation as biomarkers and therapeutic targets in AIS.
- Provided insights into molecular mechanisms underlying stroke pathophysiology and recovery.
