Experimental Ischemic Stroke-Induced Alpha-Synuclein Pathology Enhances Endothelial Inflammatory Response and Impairs...

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alpha-synuclein (α-Syn) aggregation is implicated in ischemic brain damage, but its precise role in stroke pathophysiology remains unclear.
• Investigating ischemia-induced α-Syn pathology is crucial for understanding stroke mechanisms and developing targeted therapies.

Purpose of the Study:

• To explore the impact of ischemia-induced α-Syn pathology on vascular inflammation and angiogenesis following stroke.
• To elucidate the mechanisms by which α-Syn influences stroke outcomes.

Main Methods:

• Transient focal cerebral ischemia was induced in wild-type and α-Syn-deficient mice.
• Stroke outcomes were assessed via sensorimotor tests, elevated plus maze, and survival analysis.
• Gene expression, protein oligomerization, and cellular infiltration were analyzed using molecular and histological techniques. In vitro studies used brain microvascular endothelial cells.

Main Results:

• Cerebral ischemia increased α-Syn gene expression and protein oligomerization around cortical vessels.
• α-Syn-deficient mice exhibited improved survival and functional recovery, with reduced vascular inflammation and leukocyte infiltration.
• α-Syn-deficient mice showed enhanced angiogenesis in the subacute phase, indicated by upregulated proangiogenic factors and vessel formation. In vitro, α-Syn exposure increased inflammatory and angiogenic gene expression in endothelial cells.

Conclusions:

• Ischemia-triggered pathological α-Syn exacerbates stroke outcomes by promoting acute-phase endothelial inflammation and immune cell infiltration.
• Pathological α-Syn also impairs subacute-phase angiogenesis, contributing to worse functional recovery.
• Targeting α-Syn may offer a therapeutic strategy to mitigate stroke-induced brain damage.