Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases

Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS)....

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Published inDisease models & mechanisms Vol. 5; no. 6; pp. 746 - 755
Main Author Vance, Jean E
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Ltd 01.11.2012
The Company of Biologists Limited
The Company of Biologists
Subjects
Alzheimer's disease
Animals
Biosynthesis
Blood-brain barrier
Brain
Brain - metabolism
Brain - pathology
Cholesterol
Cholesterol - metabolism
Enzymes
Homeostasis
Humans
Lipoproteins
Low density lipoprotein receptors
Mammals
Metabolism
Models, Biological
Neurodegeneration
Neurodegenerative Diseases - metabolism
Neurodegenerative Diseases - pathology
Neurons
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Abstract Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.
AbstractList Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.
Summary Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.
Author Vance, Jean E
AuthorAffiliation 1 Group on the Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, T6G 2S2, Canada
AuthorAffiliation_xml – name: 1 Group on the Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, T6G 2S2, Canada
Author_xml – sequence: 1
  givenname: Jean E
  surname: Vance
  fullname: Vance, Jean E
  email: jean.vance@ualberta.ca
  organization: Group on the Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, T6G 2S2, Canada. jean.vance@ualberta.ca
BackLink https://www.ncbi.nlm.nih.gov/pubmed/23065638$$D View this record in MEDLINE/PubMed
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Snippet Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer's disease (AD),...
Summary Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s...
Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer’s disease (AD),...
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SubjectTerms Alzheimer's disease
Animals
Biosynthesis
Blood-brain barrier
Brain
Brain - metabolism
Brain - pathology
Cholesterol
Cholesterol - metabolism
Enzymes
Homeostasis
Humans
Lipoproteins
Low density lipoprotein receptors
Mammals
Metabolism
Models, Biological
Neurodegeneration
Neurodegenerative Diseases - metabolism
Neurodegenerative Diseases - pathology
Neurons
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Title Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases
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