Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal

Abstract

Unesterified cholesterol is an essential structural component of the plasma membrane of every cell. During evolution, this membrane came to play an additional, highly specialized role in the central nervous system (CNS) as the major architectural component of compact myelin. As a consequence, in the human the mean concentration of unesterified cholesterol in the CNS is higher than in any other tissue ( ‫ف‬ 23 mg/g). Furthermore, even though the CNS accounts for only 2.1% of body weight, it contains 23% of the sterol present in the whole body pool. In all animals, most growth and differentiation of the CNS occurs in the first few weeks or years after birth, and the cholesterol required for this growth apparently comes exclusively from de novo synthesis. Currently, there is no evidence for the net transfer of sterol from the blood into the brain or spinal cord. In adults, the rate of synthesis exceeds the need for new structural sterol, so that net movement of cholesterol out of the CNS must take place. At least two pathways are used for this excretory process, one of which involves the formation of 24( S )-hydroxycholesterol. Whether or not changes in the plasma cholesterol concentration alter sterol metabolism in the CNS or whether such changes affect cognitive function in the brain or the incidence of dementia remain uncertain at this time.

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

“…The human brain is the largest repository of cholesterol in the body,1 so, not surprisingly, cholesterol homeostasis altered in the pathology of Alzheimer's disease (AD) 2. Adding to this unique lipid environment is the synthesis of cholesterol within the brain, predominantly in glial cells, without significant import from the liver 3.…”

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

“…1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models.…”

Lipid rafts, cholesterol, and the brain

“…Cholesterol biosynthesis starts with acetylCoA as a substrate and involves at least 20 enzymes (Dietschy and Turley 2001;Dietschy and Turley 2004). The rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr; EC 2.3.3.10) which catalyzes conversion of Hmg-CoA to mevalonic acid.…”

“…Although the human brain only accounts for about 2% of total body weight, it contains as much as 25% of cholesterol and cholesterol derivatives (Dietschy and Turley 2001;Dietschy and Turley 2004). Given the abundance of cholesterol in the brain, it is only natural to ask what function lipid rafts play in the CNS.…”