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Free keywords:
EAE; OPC; cholesterol; cuprizone; demyelination; knockout; multiple sclerosis; myelin; neuron; oligodendrocyte.
Abstract:
Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelin-
ating lesions, astrocytes downregulate cholesterol synthesis, and the cholesterol that is essential for remye-
lination has to originate from other cellular sources. Here, we show that repair following acute versus chronic
demyelination involves distinct processes. In particular, in chronic myelin disease, when recycling of lipids is
often defective, de novo neuronal cholesterol synthesis is critical for regeneration. By gene expression
profiling, genetic loss-of-function experiments, and comprehensive phenotyping, we provide evidence
that neurons increase cholesterol synthesis in chronic myelin disease models and in patients with multiple
sclerosis (MS). In mouse models, neuronal cholesterol facilitates remyelination specifically by triggering
oligodendrocyte precursor cell proliferation. Our data contribute to the understanding of disease progression
and have implications for therapeutic strategies in patients with MS.
