Document Detail


Regulation of cholesterol efflux by amyloid beta secretion.
MedLine Citation:
PMID:  20155813     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Amyloid beta (Abeta) is a key molecule in the pathogenesis of Alzheimer's disease, but its physiological function remains unclear. Abeta is produced from amyloid precursor protein (APP) by beta- and gamma-secretases, which is enhanced by high levels of cellular cholesterol, so cholesterol is a risk factor for Alzheimer's disease. This linkage led us to hypothesize that Abeta is produced to regulate cellular cholesterol levels in response to high-cholesterol stimulation. Here we show that Abeta production caused a reduction of cellular cholesterol levels in transfected HEK293 cells and neuronal IMR-32 and Neuro2a cells, which was accompanied by an increase in efflux of cholesterol from cells. Fractionation of the culture media by ultracentrifugation and subsequent immunoelectron microscopic observation revealed that Abeta assembled high-density lipoprotein-like particles with cellular cholesterol during its secretion. This assembly was mediated by the ATP-binding cassette transporter A1. APP transgenic and knockout mice exhibited lower and higher levels of cellular cholesterol in their brains, suggesting that Abeta-mediated regulation of cellular cholesterol is physiological. Furthermore, we found that, when injected into mouse cerebral ventricle, reconstituted lipoproteins with Abeta were excreted into the peripheral tissues more efficiently than those without Abeta. This result suggests that Abeta mediates cholesterol transport from the brain to the circulation. We propose, based on these findings, a novel, apolipoprotein-like function for Abeta that is involved in maintenance of cellular and cerebral cholesterol homeostasis.
Authors:
Tomohiro Umeda; Hiroshi Mori; Hui Zheng; Takami Tomiyama
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neuroscience research     Volume:  88     ISSN:  1097-4547     ISO Abbreviation:  J. Neurosci. Res.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-05-17     Completed Date:  2010-09-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7600111     Medline TA:  J Neurosci Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1985-94     Citation Subset:  IM    
Affiliation:
Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / metabolism
Amyloid beta-Protein / genetics,  metabolism,  secretion*
Amyloid beta-Protein Precursor / genetics,  metabolism,  secretion
Animals
Blood-Brain Barrier / metabolism
Brain / metabolism
Cell Line
Cell Line, Tumor
Cholesterol / metabolism*
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Immunoelectron
Neurons / metabolism,  ultrastructure
Receptors, Cell Surface / genetics,  metabolism
Chemical
Reg. No./Substance:
0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/Receptors, Cell Surface; 0/protease nexins; 57-88-5/Cholesterol

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