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Updated: Jul 22, 2026
A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
Growth arrest specific protein 6 alleviated white matter injury after experimental ischemic stroke
Junqiu Jia1, Siyi Xu2, Jinglong Hu1
1Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Abstract:
Ischemic white matter injury leads to long-term neurological deficits and lacks effective medication. Growth arrest specific protein 6 (Gas6) clears myelin debris, which is hypothesized to promote white matter integrity in experimental stroke models. By the middle cerebral artery occlusion (MCAO) stroke model, we observed that Gas6 reduced infarcted volume and behavior deficits 4 weeks after MCAO. Compared with control mice, Gas6-treatment mice represented higher FA values in the ipsilateral external capsules by MRI DTI scan. The SMI32/MBP ratio of the ipsilateral cortex and striatum was profoundly alleviated by Gas6 administration. Gas6-treatment group manifested thicker myelin sheaths than the control group by electron microscopy. We observed that Gas6 mainly promoted OPC maturation, which was closely related to microglia. Mechanically, Gas6 accelerated microglia-mediated myelin debris clearance and cholesterol transport protein expression (abca1, abcg1, apoc1, apoe) in vivo and in vitro, accordingly less myelin debris and lipid deposited in Gas6 treated stroke mice. HX531 (RXR inhibitor) administration mitigated the functions of Gas6 in speeding up debris clearance and cholesterol transport protein expression. Generally, we concluded that Gas6 cleared myelin debris and promoted cholesterol transportation protein expression through activating RXR, which could be one critical mechanism contributing to white matter repair after stroke.
Insights
Growth arrest specific protein 6 (Gas6) aids white matter repair after stroke by clearing debris and enhancing myelin sheath thickness. This protein activates RXR, promoting cholesterol transport and improving neurological function in stroke models.
Area of Science:
- Neuroscience
- Biochemistry
- Regenerative Medicine
Background:
- Ischemic white matter injury causes lasting neurological deficits with limited treatment options.
- Growth arrest specific protein 6 (Gas6) is a potential therapeutic agent for white matter repair due to its role in myelin debris clearance.
Purpose of the Study:
- To investigate the therapeutic potential of Gas6 in a middle cerebral artery occlusion (MCAO) stroke model.
- To elucidate the mechanisms by which Gas6 promotes white matter integrity and repair post-stroke.
Main Methods:
- Utilized the MCAO stroke model in mice.
- Assessed neurological deficits, infarct volume, and white matter integrity using MRI DTI and electron microscopy.
- Investigated Gas6's effect on oligodendrocyte precursor cell (OPC) maturation, microglia function, and cholesterol transport protein expression.
- Examined the role of RXR (retinoid X receptor) using HX531 (RXR inhibitor).
Main Results:
- Gas6 treatment significantly reduced infarct volume and improved behavioral deficits 4 weeks post-MCAO.
- MRI DTI revealed higher fractional anisotropy (FA) in Gas6-treated mice, indicating improved white matter integrity.
- Gas6 administration led to thicker myelin sheaths, reduced SMI32/MBP ratio, and enhanced expression of cholesterol transport proteins (abca1, abcg1, apoc1, apoe).
- Gas6 promoted microglia-mediated myelin debris clearance and OPC maturation, with effects mitigated by RXR inhibition.
Conclusions:
- Gas6 effectively promotes white matter repair after ischemic stroke by clearing myelin debris and enhancing cholesterol transport.
- Gas6's mechanism involves the activation of RXR, highlighting a novel therapeutic pathway for stroke recovery.
- Gas6 demonstrates significant potential as a therapeutic agent for mitigating long-term neurological deficits caused by ischemic white matter injury.
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