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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gimpl, G. Lammich, S. Kojro, E. Marz, W. Fahrenholz, F. |
| Description | Author Affiliation: Kojro E ( Institute of Biochemistry, Johannes Gutenberg University, Becherweg 30, D-55128 Mainz, Germany. kojro@mail.uni-mainz.de); |
| Abstract | Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the alpha-secretase ADAM 10 (a disintegrin and metalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-beta-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted alpha-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increased in cells overexpressing ADAM 10. In cells overexpressing APP, the increase of alpha-secretase activity resulted in a decreased secretion of Abeta peptides. Several mechanisms were elucidated as being the basis of enhanced alpha-secretase activity: increased membrane fluidity and impaired internalization of APP were responsible for the effect observed with methyl-beta-cyclodextrin; treatment with lovastatin resulted in higher expression of the alpha-secretase ADAM 10. Our results demonstrate that cholesterol reduction promotes the nonamyloidogenic alpha-secretase pathway and the formation of neuroprotective alpha-secretase cleaved soluble APP by several mechanisms and suggest approaches to prevention of or therapy for Alzheimer's disease. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 10 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amyloid Beta-Protein Precursor Biosynthesis Cholesterol Physiology Membrane Proteins Metabolism Metalloendopeptidases ADAM Proteins Amyloid Precursor Protein Secretases Anticholesteremic Agents Pharmacology Cell Compartmentation Cell Membrane Enzymology Endocytosis Hydroxymethylglutaryl-CoA Reductase Inhibitors Lovastatin Membrane Fluidity Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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