24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases

Abstract

Brain cholesterol is mainly involved in the cell membrane structure, in signal transduction, neurotransmitter release, synaptogenesis and membrane trafficking. Impairment of brain cholesterol metabolism was described in neurodegenerative diseases, such as Multiple Sclerosis, Alzheimer and Huntington Diseases. Since the blood-brain barrier efficiently prevents cholesterol uptake from the circulation into the brain, de novo synthesis is responsible for almost all cholesterol present there. Cholesterol is converted into 24S-hydroxycholesterol (24OHC) by cholesterol 24-hydroxylase (CYP46A1) expressed in neural cells. Plasma concentration of 24OHC depends upon the balance between cerebral production and hepatic elimination and is related to the number of metabolically active neurons in the brain. Factors affecting brain cholesterol turnover and liver elimination of oxysterols, together with the metabolism of plasma lipoproteins, genetic background, nutrition and lifestyle habits were found to significantly affect its plasma levels. Either increased or decreased plasma 24OHC concentrations were described in patients with neurodegenerative diseases. A group of evidence suggests that reduced levels of 24OHC are related to the loss of metabolically active cells and the degree of brain atrophy. Inflammation, dysfunction of BBB, increased cholesterol turnover might counteract this tendency resulting in increased levels or, in some cases, in unsignificant changes. The study of plasma 24OHC is likely to offer an insight about brain cholesterol turnover with a limited diagnostic power.