Abstract
Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders.
Highlights
Cholesterol is an essential component of both the peripheral and central nervous systems of mammals
The latter effects may be mediated by the liver X receptor (LXR) [5, 11]
Because it is known that substrate availability is a limiting factor for CYP27A1 activity, we have suggested that a possible therapeutic strategy could be to treat the patients with a cholesterol synthesis inhibitor [50]
Summary
The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ [1]. According to various in vitro studies with cultured cells, astrocytes synthesize at least 2- to 3-fold more cholesterol than neurons, and oligodendrocytes have an even higher capacity for cholesterol synthesis, at least during periods of active myelination [for a more detailed review, see ref [3]]. The 24S-OHC secreted from the neuronal cells may be of importance for regulation of cholesterol synthesis and secretion of this cholesterol in APOE-bound form from astroglia. The latter effects may be mediated by the liver X receptor (LXR) [5, 11]. The expression of CYP46A1 appears to be resistant to regulatory axes, which are known to regulate cholesterol homeostasis and bile acid synthesis [13]. In addition to APOE and APOD, there are other apolipoproteins in the brain, such as APOJ ( known as clusterin) and APOA1, that may be of importance [3]
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