Cholesterol: its regulation and role in central nervous system disorders

Abstract

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer's disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

Figure 1

Major cholesterol and apoE pathways in the CNS. Cholesterol is synthesized de novo in brain cells (neurons, astrocytes, microglial cells). Efflux of CNS cholesterol through the BBB occurs as 24(S)-hydroxycholesterol (24S-OH-C) and 27-hydroxycholesterol (27-OH-C). 24S-OH-C is produced exclusively in the CNS, 27-OH-C is produced in most organs. Unlike cholesterol, 24-S-OH-C and 27-OH-C can cross the BBB because of the hydroxylated side chains. Primarily astrocytes and microglia secrete HDL-like lipoproteins composed of cholesterol and phospholipids and apoE as the major apoprotein. ApoE is the ligand of these lipoproteins to the receptors of the LDL receptor family such as the LDL-receptor and LRP. Exchange of cholesterol and apos between CNS cells occurs via these lipoproteins. In plasma, 24S-OH-C and 27-OH-C are transported on lipoproteins such as LDL and HDL. De novo cholesterol synthesis in CNS cells can be regulated by the apoE-mediated uptake of lipoproteins via the LDL receptor family. ApoE is produced within the CNS and interacts with Aβ. The availability of cholesterol and of apoE are thought to affect amyloidogenesis and apoE (in particular the isoform apoE4) promoting the formation of amyloid fibrils from soluble Aβ in the CNS. The data for the steady state cholesterol pool have been determined from studies in healthy adults. The flux of cholesterol across the whole body is ~700 mg/day (CHOL INPUT/OUTPUT). The flux across the CNS is only 0.9% of whole body (~12 mg/day). The efflux of 24(S)-hydroxycholesterol through the BBB is limited to ~6-7 mg per day [64, 67], the daily influx of 27-hydroxycholesterol into the brain has been estimated to be ~5 mg [1]. Please note that the brain per kg organ contains 10 times more cholesterol than the rest of the body.