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A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia
Thorsten Trapp1, Laura Korhonen, Michael Besselmann
1Department of Experimental Neurology, Max Planck Institute for Neurological Research, Gleueler Strasse 50, 50931, Cologne, Germany.
Abstract:
X-chromosome linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis protein (IAP) family and known to inhibit death of various cells under different experimental conditions. Although present in brain tissue, little is known about the physiology of the IAPs in nerve cells. Here we report on the establishment of transgenic mice with overexpression of human XIAP in brain neurons. The mice developed normally, and were more resistant to brain injury caused by transient forebrain ischemia after occlusion of the middle cerebral artery compared to control mice. The XIAP transgenic animals exhibited significantly smaller brain damage, as shown by TUNEL labelling, less reduction in brain protein synthesis, and less active caspase-3 after ischemia compared with controls. Upregulation of RhoB, which is an early indicator of neurological damage, was markedly reduced in the XIAP-overexpressing mice, which had also a better neurological outcome than control animals. This together with the increase in XIAP in normal mouse brain in regions surviving the infarct demonstrates that XIAP is an important factor promoting neuronal survival after ischemia. The results suggest that interference with the levels and the activity of XIAP in neurons may provide targets for the development of drugs limiting neuronal death after ischemia, and possibly in other brain injuries.
Insights
Overexpressing X-chromosome linked inhibitor of apoptosis protein (XIAP) in brain neurons protected against ischemic injury. XIAP reduced brain damage and improved neurological outcomes, suggesting its therapeutic potential for brain injury.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- The X-chromosome linked inhibitor of apoptosis protein (XIAP) is crucial for inhibiting cell death.
- Its role in neuronal physiology and protection against brain injury remains largely unexplored.
Purpose of the Study:
- To investigate the physiological role of XIAP in brain neurons.
- To determine the neuroprotective effects of XIAP overexpression in a mouse model of ischemic stroke.
Main Methods:
- Generation of transgenic mice overexpressing human XIAP in brain neurons.
- Induction of transient forebrain ischemia via middle cerebral artery occlusion.
- Assessment of brain damage using TUNEL labeling, protein synthesis assays, and caspase-3 activity measurements.
- Evaluation of neurological outcomes and RhoB expression levels.
Main Results:
- XIAP transgenic mice showed significantly reduced brain damage and neuronal cell death after ischemia compared to controls.
- Overexpression of XIAP led to less reduction in brain protein synthesis and lower active caspase-3 levels.
- XIAP overexpression markedly reduced the upregulation of RhoB, an early marker of neurological damage, and improved neurological function.
Conclusions:
- XIAP is a key factor in promoting neuronal survival following ischemic injury.
- Targeting XIAP levels or activity in neurons may offer a promising therapeutic strategy for limiting neuronal death in ischemic stroke and other brain injuries.
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