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.

Keywords: cholesterol; lipid rafts; neurodegenerative disease; oxysterols; synaptic transmission.

Fig. 1

Cholesterol synthesis and oxysterol formation. Cholesterol is produced from acetyl-coenzyme A in a multistage enzymatic process. There are two pathways for cholesterol synthesis; the Bloch and Kandutsch-Russel pathways. De novo synthesized cholesterol can accumulate as cholesterol esters or be modified by enzymic or non-enzymic oxidation into oxysterols. A wide array of oxysterols have been described, each of which may have a specific effect on cellular functions. See text for a detailed explanation.

Fig. 2

Brain cholesterol metabolism: neuron–glial interplay. The major input of cholesterol into the brain comes from in situ synthesis in the endoplasmic reticulum (ER) of astrocytes. The proteins INSIG, SREBP, and SCAP regulate the cholesterol biosynthetic machinery. These proteins are tightly associated and retained in the ER at high levels of sterols. When sterol levels drop below a threshold, the complex dissociates, allowing SREBP and SCAP to translocate to the Golgi apparatus. Within this organelle, SCAP cleaves SREBP, releasing the active transcription factor, which then migrates to the nucleus to activate the genes involved in cholesterol synthesis and trafficking. Lipoprotein particles, including apolipoproteins E (ApoE), assembled in the ER are targeted to endosomes for secretion into the extracellular space. Newly synthesized cholesterol is transported from the ER to endosomes or extracellular space by non-vesicular mechanisms via ATP-binding cassette transporters (ABCA1). Cholesterol-rich ApoE-particles interact with the neuronal receptors (LRP1), undergo internalization by receptor-mediated endocytosis, and are routed to late endosomes/lysosomes. Once there, NPC1 /2 proteins promote trafficking of cholesterol to the plasma membrane or the ER. The supply of the plasma membrane with cholesterol requires caveolin-1 (Cav-1). Membrane cholesterol could be processed by CYP46A1 to 24-hydroxycholesterol (24-HC), which passes through the blood-brain barrier (BBB) and binds to light or high density lipoproteins (LDL or HDL). Increased plasma levels of 24-HC can oxidize the plasma lipoproteins (O-LP) that are then accumulated in leukocytes via scavenger receptor (SR) mediated endocytosis. Binding of 24HC to the cytoplasmic LX-receptors of astrocytes (or neurons) triggers expression of the genes (ApoE and ABCA1) involved in cholesterol trafficking from astrocytes to neurons. A certain amount of cholesterol can exit the brain through the BBB in the form of ApoA1-partciles. Elevated cholesterol content in the ER upregulates an ACAT1-dependent generation of cholesterol esters, which build up in the cytoplasm as lipid drops. SCD (stearoyl-CoA desaturase) supplies the monounsaturated fatty acids required for cholesterol esterification. Accumulation of cholesterol esters (as ApoE-particles, ApoE-ChE) in the extracellular space is associated with LCAT (lecithin–cholesterol acyltransferase) activity secreted by astrocytes. Mitochondria of many cells (in particular, macrophages) have the enzyme CYP27A1 that catalyzes the conversion of cholesterol to 27-hydroxycholesterol (27-HC) that could transverse the BBB and less effectively (as compared to 24-HC) activate LX-receptors. The neuronal enzyme CYP7B1 can convert 27-HC to 7α-hydroxy-3-oxo-4-cholestenoic acid (ChA) cleared from the brain into the circulation. Although the BBB is not permeable to plasma cholesterol, BBB endothelial cells make possible cholesterol flux across the BBB via ABC transporters and LRP1 and SR.

Fig. 3

Synaptic transmission: lipid-protein interactions. The neurotransmitter is released from the synaptic vesicles upon fusion (exocytosis) with the presynaptic membrane at a specific site (termed active zone) in response to Ca²⁺ influx via potential-gated Ca-channels. The vesicle fusion is governed by proteins forming a SNARE complex (synaptobrevin, syntaxin, SNAP-25) and is dictated by numerous cholesterol-binding proteins (synaptotagmin, Munc-18, NCS-1) and signaling molecules (protein kinases, NADPH-oxidase/Nox). After fusion, the protein and lipid components of the vesicles undergo clathrin-mediated endocytosis. The vast majority of synaptic vesicles form the reserve pool, which maintains neurotransmission during prolonged synaptic activity. These vesicles are translocated into the active zone through an actin-and synapsin-dependent pathway. Glutamate released from the synaptic vesicles changes the Na⁺/Ca²⁺ conductivity of the postsynaptic membrane by activating AMPA/NMDA receptors. The surface expression of the postsynaptic receptors is dependent on the exo-and endocytotic trafficking of these receptors, which is regulated by small GTPase (Rab11) and protein kinase (Cdc42, GSK3β, phosphoinositol-3-kinase/PI-3-K). The receptor-dependent signaling is associated with many proteins (Src, ERC, Cav-1). As illustrated in Fig.2. Cholesterol molecules and its clusters are shown in black, phosphoinositol-4,5-biphosphates (PI-4,5-P₂,) in red, and cholesterol/PI-4,5-P2-binding proteins. See text for a detailed explanation.

Fig. 4

Alterations in cholesterol synthesis associated with the Smith- Lemli-Opitz syndrome: an implication in synaptic dysfunction. See text for a detailed explanation.

Fig. 5

Changes in cholesterol metabolism in Niemann Pick disease type C: the impact on synaptic transmission. See text for a detailed explanation.

Fig. 6

Influence of the mutant huntingtin on synaptic transduction and brain cholesterol metabolism. See text for a detailed explanation.