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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

Influence of the mutant huntingtin on synaptic transduction and braincholesterol metabolism. See text for a detailed explanation.
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Figure 6: Influence of the mutant huntingtin on synaptic transduction and braincholesterol metabolism. See text for a detailed explanation.

Mentions: Huntington’s disease is an autosomal dominant neurodegenerative diseaseaccompanied by cognitive and motor dysfunction. Huntington’s disease iscaused by a genetic defect leading to an expansion of a polyglutamine stretch(over 36 residues, polyglutamine expansion) in the target protein, namedhuntingtin. Striatum and cortex neurons are sensitive to the toxic property ofthe mutated protein [85].Huntington’s disease is associated with reduced cholesterol synthesis inthe brain [10]. The mutant proteinhuntingtin decreases the transcriptional activity of SREBP, downregualtingSREBPregulated genes and, in turn, the cholesterol biosynthetic pathway incortical and striatum neurons(Fig. 6). Cholesterol levelsare first affected in synaptosomal membranes and, at later stages, in myelinsheaths. Exogenous cholesterol (up to 15 μM) prevents the death ofstriatal neurons carrying the mutant protein [86].There is a strong positive correlation between longerpolyglutamine stretches and the severity of diseases and cholesterolbiosynthesis disorder [34].Huntington’s disease rodents show a dramatic age-related decline incholesterol content in brain tissue as compared to agematched healthyindividuals [86]. Cholesterol levels infibroblasts are reduced by 50%, along with lowered total plasma cholesterolconcentrations, which are detectable early in pre-manifest patients[87]. Conversely, 24-HC levels are firstelevated at the onset of diseases and later dropping due to dysfunction ofcholesterol biosynthesis in degenerating striatal neurons [10].The first increase in 24-HC content couldrepresent a response to compensate for cholesterol loss. A further decline in24-HC levels in the brain leads to reduced cholesterol synthesis because ofdownregulation of LX-receptors and, correspondingly, LX-receptor-dependentprotein expression (ABCA1, ABCG4, ApoE). Astrocytes bearing the mutanthuntingtin produce and secrete less ApoE. Such ApoE-particles are smaller insize and lipid-poor, failing both to efficiently transfer cholesterol fromastrocytes to neurons and to clear cholesterol excess from the brain [86]. LX-receptor agonists can partiallyameliorate Huntington’s disease symptoms [10]. In cholesterol-deficient cells, cholesterol and itsesters can form patches in plasma membranes and lysosomes/endosomes, due toprevention in efflux in the form of ApoE-particles and 24-HC. Aberrantcholesterol accumulation could be a result of defects in caveolin 1 trafficinduced by the mutant huntingtin[ 88].BDNF released by nerve terminals of cortical neurons in the striatum isimplicated in not only synaptic plasticity and cell survival, but alsoinduction of cholesterol synthesis in postsynaptic neurons. The mutanthuntingtin inhibits cholesterol synthesis by influencing trafficking andsecretion of BDNF [10].


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

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

Influence of the mutant huntingtin on synaptic transduction and braincholesterol metabolism. See text for a detailed explanation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837572&req=5

Figure 6: Influence of the mutant huntingtin on synaptic transduction and braincholesterol metabolism. See text for a detailed explanation.
Mentions: Huntington’s disease is an autosomal dominant neurodegenerative diseaseaccompanied by cognitive and motor dysfunction. Huntington’s disease iscaused by a genetic defect leading to an expansion of a polyglutamine stretch(over 36 residues, polyglutamine expansion) in the target protein, namedhuntingtin. Striatum and cortex neurons are sensitive to the toxic property ofthe mutated protein [85].Huntington’s disease is associated with reduced cholesterol synthesis inthe brain [10]. The mutant proteinhuntingtin decreases the transcriptional activity of SREBP, downregualtingSREBPregulated genes and, in turn, the cholesterol biosynthetic pathway incortical and striatum neurons(Fig. 6). Cholesterol levelsare first affected in synaptosomal membranes and, at later stages, in myelinsheaths. Exogenous cholesterol (up to 15 μM) prevents the death ofstriatal neurons carrying the mutant protein [86].There is a strong positive correlation between longerpolyglutamine stretches and the severity of diseases and cholesterolbiosynthesis disorder [34].Huntington’s disease rodents show a dramatic age-related decline incholesterol content in brain tissue as compared to agematched healthyindividuals [86]. Cholesterol levels infibroblasts are reduced by 50%, along with lowered total plasma cholesterolconcentrations, which are detectable early in pre-manifest patients[87]. Conversely, 24-HC levels are firstelevated at the onset of diseases and later dropping due to dysfunction ofcholesterol biosynthesis in degenerating striatal neurons [10].The first increase in 24-HC content couldrepresent a response to compensate for cholesterol loss. A further decline in24-HC levels in the brain leads to reduced cholesterol synthesis because ofdownregulation of LX-receptors and, correspondingly, LX-receptor-dependentprotein expression (ABCA1, ABCG4, ApoE). Astrocytes bearing the mutanthuntingtin produce and secrete less ApoE. Such ApoE-particles are smaller insize and lipid-poor, failing both to efficiently transfer cholesterol fromastrocytes to neurons and to clear cholesterol excess from the brain [86]. LX-receptor agonists can partiallyameliorate Huntington’s disease symptoms [10]. In cholesterol-deficient cells, cholesterol and itsesters can form patches in plasma membranes and lysosomes/endosomes, due toprevention in efflux in the form of ApoE-particles and 24-HC. Aberrantcholesterol accumulation could be a result of defects in caveolin 1 trafficinduced by the mutant huntingtin[ 88].BDNF released by nerve terminals of cortical neurons in the striatum isimplicated in not only synaptic plasticity and cell survival, but alsoinduction of cholesterol synthesis in postsynaptic neurons. The mutanthuntingtin inhibits cholesterol synthesis by influencing trafficking andsecretion of BDNF [10].

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