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

Petrov AM, Kasimov MR, Zefirov AL - Acta Naturae (2016 Jan-Mar)

Bottom Line: Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction.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.

View Article: PubMed Central - PubMed

Affiliation: Kazan Medical University, Department of Normal Physiology, Butlerova str. 49, Kazan, Russia, 420012.

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.

No MeSH data available.


Related in: MedlinePlus

Brain cholesterol metabolism: neuron–glial interplay. The major input ofcholesterol into the brain comes from in situ synthesis in theendoplasmic reticulum (ER) of astrocytes. The proteins INSIG, SREBP, and SCAPregulate the cholesterol biosynthetic machinery. These proteins are tightlyassociated and retained in the ER at high levels of sterols. When sterol levelsdrop below a threshold, the complex dissociates, allowing SREBP and SCAP totranslocate to the Golgi apparatus. Within this organelle, SCAP cleaves SREBP,releasing the active transcription factor, which then migrates to the nucleusto activate the genes involved in cholesterol synthesis and trafficking.Lipoprotein particles, including apolipoproteins E (ApoE), assembled in the ERare targeted to endosomes for secretion into the extracellular space. Newlysynthesized cholesterol is transported from the ER to endosomes orextracellular space by non-vesicular mechanisms via ATP-binding cassettetransporters (ABCA1). Cholesterol-rich ApoE-particles interact with theneuronal receptors (LRP1), undergo internalization by receptor-mediatedendocytosis, and are routed to late endosomes/lysosomes. Once there, NPC1 /2proteins 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 lightor high density lipoproteins (LDL or HDL). Increased plasma levels of 24-HC canoxidize the plasma lipoproteins (O-LP) that are then accumulated in leukocytesvia scavenger receptor (SR) mediated endocytosis. Binding of 24HC to thecytoplasmic LX-receptors of astrocytes (or neurons) triggers expression of thegenes (ApoE and ABCA1) involved in cholesterol trafficking from astrocytes toneurons. A certain amount of cholesterol can exit the brain through the BBB inthe form of ApoA1-partciles. Elevated cholesterol content in the ER upregulatesan ACAT1-dependent generation of cholesterol esters, which build up in thecytoplasm as lipid drops. SCD (stearoyl-CoA desaturase) supplies themonounsaturated fatty acids required for cholesterol esterification.Accumulation of cholesterol esters (as ApoE-particles, ApoE-ChE) in theextracellular space is associated with LCAT (lecithin–cholesterolacyltransferase) activity secreted by astrocytes. Mitochondria of many cells(in particular, macrophages) have the enzyme CYP27A1 that catalyzes theconversion of cholesterol to 27-hydroxycholesterol (27-HC) that couldtransverse the BBB and less effectively (as compared to 24-HC) activateLX-receptors. The neuronal enzyme CYP7B1 can convert 27-HC to7α-hydroxy-3-oxo-4-cholestenoic acid (ChA) cleared from the brain into thecirculation. Although the BBB is not permeable to plasma cholesterol, BBBendothelial cells make possible cholesterol flux across the BBB via ABCtransporters and LRP1 and SR.
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Figure 2: Brain cholesterol metabolism: neuron–glial interplay. The major input ofcholesterol into the brain comes from in situ synthesis in theendoplasmic reticulum (ER) of astrocytes. The proteins INSIG, SREBP, and SCAPregulate the cholesterol biosynthetic machinery. These proteins are tightlyassociated and retained in the ER at high levels of sterols. When sterol levelsdrop below a threshold, the complex dissociates, allowing SREBP and SCAP totranslocate to the Golgi apparatus. Within this organelle, SCAP cleaves SREBP,releasing the active transcription factor, which then migrates to the nucleusto activate the genes involved in cholesterol synthesis and trafficking.Lipoprotein particles, including apolipoproteins E (ApoE), assembled in the ERare targeted to endosomes for secretion into the extracellular space. Newlysynthesized cholesterol is transported from the ER to endosomes orextracellular space by non-vesicular mechanisms via ATP-binding cassettetransporters (ABCA1). Cholesterol-rich ApoE-particles interact with theneuronal receptors (LRP1), undergo internalization by receptor-mediatedendocytosis, and are routed to late endosomes/lysosomes. Once there, NPC1 /2proteins 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 lightor high density lipoproteins (LDL or HDL). Increased plasma levels of 24-HC canoxidize the plasma lipoproteins (O-LP) that are then accumulated in leukocytesvia scavenger receptor (SR) mediated endocytosis. Binding of 24HC to thecytoplasmic LX-receptors of astrocytes (or neurons) triggers expression of thegenes (ApoE and ABCA1) involved in cholesterol trafficking from astrocytes toneurons. A certain amount of cholesterol can exit the brain through the BBB inthe form of ApoA1-partciles. Elevated cholesterol content in the ER upregulatesan ACAT1-dependent generation of cholesterol esters, which build up in thecytoplasm as lipid drops. SCD (stearoyl-CoA desaturase) supplies themonounsaturated fatty acids required for cholesterol esterification.Accumulation of cholesterol esters (as ApoE-particles, ApoE-ChE) in theextracellular space is associated with LCAT (lecithin–cholesterolacyltransferase) activity secreted by astrocytes. Mitochondria of many cells(in particular, macrophages) have the enzyme CYP27A1 that catalyzes theconversion of cholesterol to 27-hydroxycholesterol (27-HC) that couldtransverse the BBB and less effectively (as compared to 24-HC) activateLX-receptors. The neuronal enzyme CYP7B1 can convert 27-HC to7α-hydroxy-3-oxo-4-cholestenoic acid (ChA) cleared from the brain into thecirculation. Although the BBB is not permeable to plasma cholesterol, BBBendothelial cells make possible cholesterol flux across the BBB via ABCtransporters and LRP1 and SR.

Mentions: De novo cholesterol synthesis begins with the transformationof acetyl-CoA into 3-hydroxyl-3-methylglutaryl- coenzyme A (HMG-CoA) via areaction catalyzed by HMG-CoA -synthetase and then by HMG-CoA reductase intomevalonate. The HMG-CoA reductase-catalyzed formation of mevalonate is anirreversible and rate-limiting step in the cholesterol biosynthesis, targetedby statin drugs. There are two cholesterologenic pathways in the brain(Fig. 1).Neurons mainly contain sterols synthesized via theKandutsch-Russel cholesterol synthetic pathway (7-dehydrocholesterol,lanosterol), and astrocytes contain precursors of the Bloch pathway(desmosterol) [10]. The machinery ofcholesterol synthesis resides in the endoplasmic reticulum (ER). Thecholesterol content in the ER shows greater variations than in plasmamembranes. Indeed, the cholesterol environment in the ER influences the totalcholesterol levels in the cell. One of the key players in cholesterolregulation is SREBP-2 (sterol-regulatory element-binding protein), an inactivetranscription factor anchored to the ER membrane and capable of binding to SCAP(SREBP cleavage-activating protein), which functions as a detector ofcholesterol due to a sterol-sensing domain. During high cholesterolconcentrations, the SREBP-2/SCAP complex is retained in the membranes of the ERby the retention proteins INSIG- 1 and -2 (insulin-induced protein 1 and 2). Insterol- depleted cells, the interaction between the INSIG retention complex andSREBP-2/SCAP is lost, allowing SCAP to escort SREBP-2 to the Golgi compartment.Within this organelle, SCAP releases the N-terminal domain of SREBP-2, whichtranslocates to the nucleus to bind sterol regulatory elements (SRE) in thepromoter regions of over 30 target genes encoding enzymes of cholesterolbiosynthesis (Fig. 2)[1, 10-12].


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

Petrov AM, Kasimov MR, Zefirov AL - Acta Naturae (2016 Jan-Mar)

Brain cholesterol metabolism: neuron–glial interplay. The major input ofcholesterol into the brain comes from in situ synthesis in theendoplasmic reticulum (ER) of astrocytes. The proteins INSIG, SREBP, and SCAPregulate the cholesterol biosynthetic machinery. These proteins are tightlyassociated and retained in the ER at high levels of sterols. When sterol levelsdrop below a threshold, the complex dissociates, allowing SREBP and SCAP totranslocate to the Golgi apparatus. Within this organelle, SCAP cleaves SREBP,releasing the active transcription factor, which then migrates to the nucleusto activate the genes involved in cholesterol synthesis and trafficking.Lipoprotein particles, including apolipoproteins E (ApoE), assembled in the ERare targeted to endosomes for secretion into the extracellular space. Newlysynthesized cholesterol is transported from the ER to endosomes orextracellular space by non-vesicular mechanisms via ATP-binding cassettetransporters (ABCA1). Cholesterol-rich ApoE-particles interact with theneuronal receptors (LRP1), undergo internalization by receptor-mediatedendocytosis, and are routed to late endosomes/lysosomes. Once there, NPC1 /2proteins 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 lightor high density lipoproteins (LDL or HDL). Increased plasma levels of 24-HC canoxidize the plasma lipoproteins (O-LP) that are then accumulated in leukocytesvia scavenger receptor (SR) mediated endocytosis. Binding of 24HC to thecytoplasmic LX-receptors of astrocytes (or neurons) triggers expression of thegenes (ApoE and ABCA1) involved in cholesterol trafficking from astrocytes toneurons. A certain amount of cholesterol can exit the brain through the BBB inthe form of ApoA1-partciles. Elevated cholesterol content in the ER upregulatesan ACAT1-dependent generation of cholesterol esters, which build up in thecytoplasm as lipid drops. SCD (stearoyl-CoA desaturase) supplies themonounsaturated fatty acids required for cholesterol esterification.Accumulation of cholesterol esters (as ApoE-particles, ApoE-ChE) in theextracellular space is associated with LCAT (lecithin–cholesterolacyltransferase) activity secreted by astrocytes. Mitochondria of many cells(in particular, macrophages) have the enzyme CYP27A1 that catalyzes theconversion of cholesterol to 27-hydroxycholesterol (27-HC) that couldtransverse the BBB and less effectively (as compared to 24-HC) activateLX-receptors. The neuronal enzyme CYP7B1 can convert 27-HC to7α-hydroxy-3-oxo-4-cholestenoic acid (ChA) cleared from the brain into thecirculation. Although the BBB is not permeable to plasma cholesterol, BBBendothelial cells make possible cholesterol flux across the BBB via ABCtransporters and LRP1 and SR.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Brain cholesterol metabolism: neuron–glial interplay. The major input ofcholesterol into the brain comes from in situ synthesis in theendoplasmic reticulum (ER) of astrocytes. The proteins INSIG, SREBP, and SCAPregulate the cholesterol biosynthetic machinery. These proteins are tightlyassociated and retained in the ER at high levels of sterols. When sterol levelsdrop below a threshold, the complex dissociates, allowing SREBP and SCAP totranslocate to the Golgi apparatus. Within this organelle, SCAP cleaves SREBP,releasing the active transcription factor, which then migrates to the nucleusto activate the genes involved in cholesterol synthesis and trafficking.Lipoprotein particles, including apolipoproteins E (ApoE), assembled in the ERare targeted to endosomes for secretion into the extracellular space. Newlysynthesized cholesterol is transported from the ER to endosomes orextracellular space by non-vesicular mechanisms via ATP-binding cassettetransporters (ABCA1). Cholesterol-rich ApoE-particles interact with theneuronal receptors (LRP1), undergo internalization by receptor-mediatedendocytosis, and are routed to late endosomes/lysosomes. Once there, NPC1 /2proteins 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 lightor high density lipoproteins (LDL or HDL). Increased plasma levels of 24-HC canoxidize the plasma lipoproteins (O-LP) that are then accumulated in leukocytesvia scavenger receptor (SR) mediated endocytosis. Binding of 24HC to thecytoplasmic LX-receptors of astrocytes (or neurons) triggers expression of thegenes (ApoE and ABCA1) involved in cholesterol trafficking from astrocytes toneurons. A certain amount of cholesterol can exit the brain through the BBB inthe form of ApoA1-partciles. Elevated cholesterol content in the ER upregulatesan ACAT1-dependent generation of cholesterol esters, which build up in thecytoplasm as lipid drops. SCD (stearoyl-CoA desaturase) supplies themonounsaturated fatty acids required for cholesterol esterification.Accumulation of cholesterol esters (as ApoE-particles, ApoE-ChE) in theextracellular space is associated with LCAT (lecithin–cholesterolacyltransferase) activity secreted by astrocytes. Mitochondria of many cells(in particular, macrophages) have the enzyme CYP27A1 that catalyzes theconversion of cholesterol to 27-hydroxycholesterol (27-HC) that couldtransverse the BBB and less effectively (as compared to 24-HC) activateLX-receptors. The neuronal enzyme CYP7B1 can convert 27-HC to7α-hydroxy-3-oxo-4-cholestenoic acid (ChA) cleared from the brain into thecirculation. Although the BBB is not permeable to plasma cholesterol, BBBendothelial cells make possible cholesterol flux across the BBB via ABCtransporters and LRP1 and SR.
Mentions: De novo cholesterol synthesis begins with the transformationof acetyl-CoA into 3-hydroxyl-3-methylglutaryl- coenzyme A (HMG-CoA) via areaction catalyzed by HMG-CoA -synthetase and then by HMG-CoA reductase intomevalonate. The HMG-CoA reductase-catalyzed formation of mevalonate is anirreversible and rate-limiting step in the cholesterol biosynthesis, targetedby statin drugs. There are two cholesterologenic pathways in the brain(Fig. 1).Neurons mainly contain sterols synthesized via theKandutsch-Russel cholesterol synthetic pathway (7-dehydrocholesterol,lanosterol), and astrocytes contain precursors of the Bloch pathway(desmosterol) [10]. The machinery ofcholesterol synthesis resides in the endoplasmic reticulum (ER). Thecholesterol content in the ER shows greater variations than in plasmamembranes. Indeed, the cholesterol environment in the ER influences the totalcholesterol levels in the cell. One of the key players in cholesterolregulation is SREBP-2 (sterol-regulatory element-binding protein), an inactivetranscription factor anchored to the ER membrane and capable of binding to SCAP(SREBP cleavage-activating protein), which functions as a detector ofcholesterol due to a sterol-sensing domain. During high cholesterolconcentrations, the SREBP-2/SCAP complex is retained in the membranes of the ERby the retention proteins INSIG- 1 and -2 (insulin-induced protein 1 and 2). Insterol- depleted cells, the interaction between the INSIG retention complex andSREBP-2/SCAP is lost, allowing SCAP to escort SREBP-2 to the Golgi compartment.Within this organelle, SCAP releases the N-terminal domain of SREBP-2, whichtranslocates to the nucleus to bind sterol regulatory elements (SRE) in thepromoter regions of over 30 target genes encoding enzymes of cholesterolbiosynthesis (Fig. 2)[1, 10-12].

Bottom Line: Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction.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.

View Article: PubMed Central - PubMed

Affiliation: Kazan Medical University, Department of Normal Physiology, Butlerova str. 49, Kazan, Russia, 420012.

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.

No MeSH data available.


Related in: MedlinePlus