Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction

Abstract

Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body’s total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington’s, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer’s disease, Parkinson’s disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

Cholesterol in the Pathogenesis of Alzheimer’s, Parkinson’s Diseases and Autism: Link to Synaptic Dysfunction

“…Individuals with elevated plasma 24OH-Ch have a higher probability of developing cognitive impairment over the next 8 years [12]. The excessive production of 24OH-Ch may be an indication of an attempt to compensate for the nascent dysfunction [1]. Elevated expression of the 24OH-Ch-synthesizing enzyme CYP46A1 (using adenoviral therapy) in the brain of APP23-mice significantly reduces Aβ accumulation, gliosis, and cognitive defects [13].…”

“…Elevated expression of the 24OH-Ch-synthesizing enzyme CYP46A1 (using adenoviral therapy) in the brain of APP23-mice significantly reduces Aβ accumulation, gliosis, and cognitive defects [13]. The effect of CYP46A1 activation may be mediated by 24OH-Ch that stimulates LXα and β-receptors, which, in turn, increases the expression of the genes involved in cholesterol synthesis and traffic [1]. Deletion of LXα or β-receptor genes causes age-related neurodegenerative disorders [14].…”

“…These observations suggest the existence of an Aβ-dependent mechanism of cholesterol removal from the nerve terminal membrane. Other ways of lowering brain cholesterol availability in patients with AD can be associated with: APP/Aβ-dependent supression of cholesterol synthesis by inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-reductase) [24]; decrease in the uptake of cholesterol-loaded ApoE-particles under the influence of Aβ [15]; increase in cholesterol oxidation due to enhanced CYP46A1 activity [11]; Aβ-induced modification of lipid rafts [1, 25]. The increase in CYP46A1 activity may be caused by Aβ-induced alterations in Ca 2+ homeostasis and oxidative stress [11, 26].…”

“…Previously, we described changes in cholesterol metabolism in rare hereditary pathologies of the central nervous system caused by mutations in the genes which are directly involved in the biosynthesis of cholesterol (Smith-Lemli-Opitz syndrome) or its intracellular traffic (Niemann-Pick type C disease) and synthesis regulation (Huntington disease) [1]. In this review, we analyze the relationships between such common neurodegenerative diseases as Alzheimer’s and Parkinson’s and autism spectrum disorders and cholesterol homeostasis and synaptic dysfunction.…”

Tau Spread, Apolipoprotein E, Inflammation, and More

“…In the brain, cholesterol exists in two major pools: unesterified (free cholesterol), which accounts for 95% of cholesterol in the brain, and the esterified cholesterol, which constitutes 5% of total cholesterol. Free cholesterol resides in cell membranes and functions in cellular membrane fluidity, electrical transduction, structure, repair, and permeability 37 . Conversely, esterified cholesterol is found intracellularly and is sequestered into lipid droplets.…”