Posted by The central nervous system ( CNS) is increasingly recognized as a cholesterol-rich organ. While the brain accounts for approximately 5% of total body weight, it contains around 25% of the body’s total cholesterol, which is kept separate from peripheral sources by the blood brain barrier (BBB). In addition, many diseases of the CNS are associated with dysregulated cholesterol homeostasis. In this paper, the generation of cholesterol in the CNS and its physiological roles in myelination and neurodevelopment were reviewed.
Proper regulation of cholesterol metabolism and processing is critical, as its dysregulation is associated with several neurological disorders, including multiple sclerosis. Ongoing research is exploring therapeutic strategies to address cholesterol dysregulation as it pertains to remyelination and neuroinflammation. The lipid-related therapeutics targeting neuroinflammation and remyelination include statins, cyclodextrins and LXR, RXR agonists (see the figure below).
Mechanisms of therapies that target lipid metabolism. (A) In the periphery, statins decrease cholesterol levels by inhibiting the rate-limiting step in cholesterol synthesis. (B) In the CNS, statins reduce T cell proliferation and decrease their MHC II expression. (C) Cyclodextrins upregulate the expression of lipid metabolism genes, including ABCA1, ABCG1, Trem2 and ApoE. (D) Cyclodextrins promote the dissolution of cholesterol crystals, thereby inhibiting crystal-induced ROS production and complement activation. (E) Cyclodextrins enhance autophagy, increase cathepsin D protease activity, and reduce lysosomal stress. (F-H) Cyclodextrins stimulate lysosomal exocytosis of cholesterol, transferring it into the metabolically active cholesterol pool. From there, cholesterol can either be esterified (G) or exported (H). (I) LXR agonists activate LXR signalling pathways, promoting the expression of LXR target genes. (I) LXR agonists reduce cholesterol crystal accumulation within macrophages. (K) RXR agonists, such as bexarotene, enhance the phagocytosis of myelin debris by macrophages.
Wuerch, E.C., Yong, V.W. Cholesterol in the CNS: functions, recycling and remyelination. J Neuroinflammation 22, 180 (2025). https://doi.org/10.1186/s12974-025-03490-8