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White matter injury due to experimental chronic cerebral hypoperfusion is associated with C5 deposition
Qinghai Liu1, Shuhan He2, Leonid Groysman2
1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Insights
The C5 complement protein contributes to white matter injury in chronic cerebral hypoperfusion. Reducing C5 levels decreases inflammation and ischemia in the brain.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- The C5 complement protein is a key inflammatory mediator implicated in stroke and neurodegenerative diseases.
- Microvascular failure is a proposed mechanism contributing to brain injury.
Purpose of the Study:
- To investigate the role of C5 in white matter injury during chronic cerebral hypoperfusion.
- To determine if C5 contributes to inflammation and ischemia in the corpus callosum.
Main Methods:
- Induction of bilateral carotid artery stenosis in mice to model chronic cerebral hypoperfusion.
- Measurement of C5 protein deposition in the corpus callosum.
- Comparison of white matter injury, reactive astrocytes, and microglia in C5-deficient versus C5-sufficient mice.
Main Results:
- C5 protein deposition increased in the corpus callosum over 30 days post-stenosis, correlating with white matter injury.
- Systemic serum C5 levels did not change, suggesting a localized cerebral role.
- C5-deficient mice showed significantly reduced white matter ischemia and neuroinflammation compared to controls.
Conclusions:
- C5 complement protein plays a critical role in mediating white matter injury in chronic cerebral hypoperfusion.
- Targeting C5 may offer a therapeutic strategy for conditions involving cerebral hypoperfusion and associated white matter damage.
Abstract:
The C5 complement protein is a potent inflammatory mediator that has been implicated in the pathogenesis of both stroke and neurodegenerative disease. Microvascular failure is proposed as a potential mechanism of injury. Along these lines, this investigation examines the role of C5 in the setting of chronic cerebral hypoperfusion. Following experimental bilateral carotid artery stenosis, C5 protein deposition increases in the corpus callosum over thirty days (p<0.05). The time course is temporally consistent with the appearance of white matter injury. Concurrently, systemic serum C5 levels do not appear to differ between bilateral carotid artery stenosis and sham-operated mice, implicating a local cerebral process. Following bilateral carotid artery stenosis, C5 deficient mice demonstrate decreased white matter ischemia in the corpus callosum when compared to C5 sufficient controls (p<0.05). Further, the C5 deficient mice exhibit fewer reactive astrocytes and microglia (p<0.01). This study reveals that the C5 complement protein may play a critical role in mediating white matter injury through inflammation in the setting of chronic cerebral hypoperfusion.
