27-Hydroxycholesterol Promotes Oligodendrocyte Maturation – Implications for Hypercholesterolemia Associated Brain White Matter Changes

Abstract

Background: Midlife hypercholesterolemia is a risk factor for dementia, possibly via vascular-related pathways. Another proposed factor linking elevated systemic cholesterol levels and neurodegenerative diseases is the oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) that is able to pass the blood-brain barrier. High levels of 27-OH harm neuronal integrity and function, yet the effect of high 27-OH levels on oligodendrocyte function remains unexplored. Since abnormal myelin structure results in the disconnection of neural networks that is an early phenomenon in neurodegenerative diseases, this study aimed to determine whether 27-OH affects myelination in the brain. Methods: Effects of 27-OH treatment were investigated both in isolated and co-cultured oligodendrocytes. Transgenic female mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioural testing and their brains were immunohistochemically stained and lysed for immunoblotting. CSF samples from a memory clinic cohort were analysed for associations between 27-OH and myelin proteins. Results: Whereas human oligodendroglioma cells were resistant to high levels of 27-OH (10 µM), cell death was induced in primary rat oligodendrocytes already at low concentrations (0.5 µM). Long-term effects from treatment with 1 µM 27-OH stimulated differentiation of oligodendrocytes in murine 3D co-cultures. Female Cyp27Tg mice demonstrated learning deficits in the Morris Water Maze compared to non-transgenic littermates. Levels of myelin basic protein were increased in the corpus callosum of Cyp27Tg mice but adenomatous polyposis coli clone 1 (CC1) and platelet-derived growth factor receptor α (PDGFR1α) were unaltered, while levels of myelin oligodendrocyte glycoprotein were decreased in myelin enriched fractions. Levels of 27-OH in the CSF of memory clinic patients were associated with increased levels of the oligodendrogenesis regulating enzyme 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase; β = 0.38, p = 0.022). Conclusions: The hypercholesterolemia associated 27-OH alters the rate of differentiation from progenitor cells into mature oligodendrocytes and influences oligodendrocyte viability suggesting that 27-OH reduces the oligodendrocytic ability for appropriate remodelling in the ageing brain by reducing the pool of progenitor cells.