Brain cholesterol metabolism and neurologic disease

Abstract

ABC= : ATP binding cassette; ABCA1= : ABC transporter protein family member A1; AD= : Alzheimer disease; apoE= : apolipoprotein E; APP= : amyloid precursor protein; ATP= : adenosine triphosphate; CoA= : coenzyme A; CYP= : cytochrome P; 7-DHC= : 7-dehydrocholesterol; ER= : endoplasmic reticulum; HD= : Huntington disease; HDL= : high-density lipoprotein; HMG-CoA= : 3-hydroxy-3-methyglutaryl-CoA; HMGR= : HMG-CoA reductase; LDLR= : low-density lipoprotein receptors; LTP= : long-term potentiation; LXR= : liver X-activated receptor; NMDA= : N-methyl-d-aspartate; NPC= : Niemann-Pick type C; 24-OHC= : 24-hydroxy cholesterol; SHH= : sonic hedgehog; SRE-1= : sterol-regulated element-1; SREBP= : sterol-regulated element binding protein. The human brain accounts for 2% of the whole body mass, yet it contains approximately 25% of the total cholesterol of the body. Cholesterol is a major lipid constituent of the myelin sheath and the membrane lipid rafts in neurons and astrocytes. It has an important role in brain development and neuronal function by regulating cell signaling pathways, gene transcription, and availability of bioactive steroids.1–4 Cholesterol synthesis and metabolism in the brain involve complex interactions between astrocytes and neurons.1–4 Abnormalities in cholesterol metabolism in the CNS occur in several neurologic disorders, including Niemann-Pick type C5 and Smith-Lemli-Opitz syndrome.6 Prominent neurologic manifestations also occur in disorders of peripheral cholesterol metabolism, such as cerebrotendinous xanthomatosis7 and Tangier disease.8 Brain cholesterol has also been implicated in the pathogenesis of Alzheimer disease (AD)2,3,9–11 and Huntington disease.12 The metabolism of cholesterol in the brain and its implications for neurologic disease have been extensively reviewed.1–4,10–12 Cholesterol is a crucial component of mammalian membranes. Most brain cholesterol is unesterified and primarily localized in myelin sheaths. Cholesterol is also concentrated in plasma membrane domains called lipid rafts13,14 in neurons and astrocytes. The cholesterol content of the CNS is largely independent of dietary uptake or hepatic synthesis, as circulating cholesterol does not cross the blood–brain barrier. Brain cholesterol turnover is extremely slow, with a half-life estimated in years in humans.1,4 ### Synthesis and recycling. Neurons need to maintain the large membrane surface of their dendritic processes and axonal projections. In addition, cholesterol concentration at the lipid rafts critically regulates ion channel permeability, signal transduction, synaptogenesis, and synaptic vesicle dynamics.13,14 Thus a tight control of cholesterol homeostasis is critical for neuronal function. Although neurons can synthesize cholesterol, astrocytes are the main source of cholesterol for neurons1,4 (figure). The first steps of …