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A Morphological and Behavioral Study of Demyelination and Remyelination in the Cuprizone Model: Insights into APLNR
Boycho Landzhov1, Lyubomir Gaydarski1, Stancho Stanchev1
1Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria.
Abstract:
Multiple sclerosis (MS) is a chronic neurodegenerative disorder involving demyelination. The cuprizone model is commonly used to study MS by inducing oligodendrocyte stress and demyelination. The subventricular zone (SVZ) plays a key role in neurogenesis, while the neuronal/glial antigen 2 (NG2) is a marker for immature glial cells, involved in oligodendrocyte differentiation. The apelin receptor (APLNR) is linked to neurogenesis and behavior modulation. This study explores the role of APLNR in NG2-positive cells during de- and remyelination phases in the experimental cuprizone mouse model. Thirty male C57BL/6 mice were divided into control (not treated), demyelination (5 weeks cuprizone administration), and remyelination (5 weeks cuprizone administration + 5 weeks recovery) groups. Histological examinations, immunohistochemistry, and immunofluorescence on serial coronal sections were conducted to evaluate corpus callosum (CC) morphology and APLNR and NG2 expression in the SVZ, in addition to behavioral assessments. The histological analysis showed a significant reduction in the CC's thickness and area after five weeks of cuprizone exposure, followed by recovery five weeks post-exposure. During the demyelination phase, APLNR-expressing cells peaked while NG2-positive cells decreased. In the remyelination phase, APLNR-expressing cells declined, and NG2-positive cells increased. Confocal microscopy confirmed the co-localization of NG2 and APLNR markers. Statistically significant differences were observed across experimental groups. Correlation analyses highlighted associations between APLNR/NG2 cell counts and CC changes. Behavioral tests revealed impaired motor coordination and memory during demyelination, with gradual recovery during remyelination. Significant changes in the CC structure and the number of APLNR and NG2-positive cells were observed during de- and remyelination, suggesting that NG2-positive cells expressing APLNR may play a key role in remyelination.
Insights
The apelin receptor (APLNR) on NG2-positive cells is crucial for remyelination in a mouse model of multiple sclerosis (MS). APLNR expression changes correlate with myelin repair and behavioral recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by demyelination.
- The cuprizone model is widely used to study MS pathology, inducing oligodendrocyte damage and demyelination.
- The subventricular zone (SVZ) is a neurogenic niche, and NG2 marks oligodendrocyte precursor cells vital for myelin repair.
Purpose of the Study:
- To investigate the role of the apelin receptor (APLNR) in NG2-positive cells during demyelination and remyelination in the cuprizone mouse model.
- To assess the correlation between APLNR expression, NG2-positive cell dynamics, corpus callosum (CC) integrity, and behavioral outcomes.
Main Methods:
- Utilized the cuprizone-induced demyelination/remyelination mouse model.
- Conducted histological and immunofluorescence analyses to evaluate CC morphology and APLNR/NG2 expression in the SVZ.
- Performed behavioral assessments to measure motor coordination and memory.
Main Results:
- Cuprizone exposure led to significant CC thinning and area reduction, with partial recovery post-treatment.
- APLNR-expressing cells increased during demyelination, while NG2-positive cells decreased; the opposite occurred during remyelination.
- Co-localization of NG2 and APLNR was confirmed, and cell counts correlated with CC changes and behavioral recovery.
Conclusions:
- NG2-positive cells expressing APLNR are dynamically regulated during demyelination and remyelination.
- APLNR signaling in NG2-positive cells appears to play a significant role in the remyelination process in MS.
- These findings suggest APLNR as a potential therapeutic target for promoting myelin repair in MS.
