Spatiotemporal APLNR Expression Dynamics During Oligodendroglial Remodeling of the Corpus Callosum in the Cuprizone Model

Demyelinating disorders such as multiple sclerosis are characterized by oligodendrocyte loss and insufficient remyelination. The cuprizone model provides a well-established experimental system for studying these processes. The apelinergic system, including the apelin receptor (APLNR), has been implicated in neuroprotection and central nervous system homeostasis. However, its role in white matter demyelination and repair remains incompletely understood. This study aimed to characterize the spatial and temporal dynamics of APLNR expression in relation to oligodendrocyte lineage cells in the corpus callosum (CC) during demyelination and remyelination. Demyelination was induced in 8-week-old C57BL/6 mice by 0.2% cuprizone supplementation in their drinking water for 5 weeks, followed by 5 weeks remyelination phase after toxin withdrawal. Histological assessment using Luxol Fast Blue/Cresyl violet staining was performed to evaluate structural changes in the CC. Immunohistochemistry and confocal microscopy were used to analyze APLNR expression, GST-π+ cells, and NG2+ cells, including their spatial distribution and co-localization. Quantitative analyses and correlation tests were conducted to assess relationships between cellular markers and CC area. Demyelination resulted in significant reduction in CC area and a marked decrease in GST-π+ cells, accompanied by a robust increase in NG2+ cells, while remyelination led to partial structural and cellular recovery. APLNR expression increased progressively from control to demyelination and further during remyelination, exhibiting pronounced regional heterogeneity with higher levels in lateral CC regions. Confocal analysis demonstrated increasing co-localization of APLNR with NG2+ cells, particularly during remyelination. Correlation analyses identified GST-π+ cell density as the strongest predictor of CC area, whereas APLNR showed phase-dependent associations, including a positive correlation with GST-π+ cells during remyelination and a negative relationship with NG2+ cells during demyelination. APLNR expression is dynamically regulated during cuprizone-induced demyelination and remyelination and is closely associated with oligodendrocyte lineage cell responses. Its increased expression and enhanced co-localization with NG2+ cells during remyelination suggest a potential role in endogenous repair processes. However, as the findings are based on descriptive analyses, further functional studies are required to determine the mechanistic contribution of APLNR signaling and its potential as a therapeutic target in demyelinating diseases.