| Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins. | |
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MedLine Citation:
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PMID: 12468034 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apolipoprotein E (ApoE) genotype modulates the risk of Alzheimer's disease. ApoE has been shown essential for amyloid beta-peptide fibrillogenesis and deposition, a defining pathological feature of this disease. Because astrocytes and microglia represent the major source of extracellular apoE in brain, we investigated apoE secretion by glia. We determined that protein prenylation is required for apoE release from a continuous microglial cell line, primary mixed glia, and from organotypic hippocampal cultures. Using selective protein prenylation inhibitors, apoE secretion was found to require protein geranylgeranylation. This prenylation involved a protein critical to apoE secretion, not apoE proper. ApoE secretion could also be suppressed by inhibiting synthesis of mevalonate, the precursor to both types of protein prenylation, using hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins). Recent reports have described the beneficial effects of statins on the risk of dementia. Our finding that protein geranylgeranylation is required for apoE secretion in the brain parenchyma provides another contributing mechanism to explain the effective properties of statins against the development of dementia. In this model, statin-mediated inhibition of mevalonate synthesis, an essential reaction in forming geranylgeranyl lipid, would lower extracellular levels of parenchymal apoE. Because apoE has been found necessary for plaque development in transgenic models of Alzheimer's disease, suppressing apoE secretion by statins could reduce plaques and, in turn, improve cognitive function. |
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Authors:
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Asha Naidu; Qiang Xu; Rosanne Catalano; Barbara Cordell |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Brain research Volume: 958 ISSN: 0006-8993 ISO Abbreviation: Brain Res. Publication Date: 2002 Dec |
Date Detail:
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Created Date: 2002-12-06 Completed Date: 2003-02-25 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0045503 Medline TA: Brain Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 100-11 Citation Subset: IM |
Copyright Information:
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Copyright 2002 Elsevier Science B.V. |
Affiliation:
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Scios Inc, 820 West Maude Avenue, Sunnyvale, CA 94085, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alkyl and Aryl Transferases
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antagonists & inhibitors,
metabolism Alzheimer Disease / drug therapy*, metabolism*, physiopathology Amyloid beta-Protein / metabolism Animals Animals, Newborn Apolipoproteins E / metabolism* Astrocytes / drug effects, metabolism, secretion Brain / drug effects, metabolism*, physiopathology Cells, Cultured Disease Models, Animal Dose-Response Relationship, Drug Farnesyltranstransferase Hippocampus / drug effects, metabolism Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology* Lovastatin / analogs & derivatives*, pharmacology Mevalonic Acid / antagonists & inhibitors, metabolism Mice Mice, Transgenic Microglia / drug effects, metabolism, secretion Neuroglia / drug effects, metabolism, secretion* Polyisoprenyl Phosphates / metabolism, pharmacology Protein Prenylation / drug effects, physiology* |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Apolipoproteins E; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Polyisoprenyl Phosphates; 150-97-0/Mevalonic Acid; 6699-20-3/geranylgeranyl pyrophosphate; 73573-88-3/compactin; 75330-75-5/Lovastatin; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.29/Farnesyltranstransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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