Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons

被引：1035
作者：
Simons, M
Keller, P
De Strooper, B
Beyreuther, K
Dotti, CG
Simons, K
机构：
[1] European Mol Biol Lab, Cell Biol Programme, D-69012 Heidelberg, Germany
[2] Catholic Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium
[3] Univ Heidelberg, Ctr Mol Biol Heidelberg, D-69120 Heidelberg, Germany
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 1998年 / 95卷 / 11期
关键词：
D O I：
10.1073/pnas.95.11.6460
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer's disease. During intracellular transport APP undergoes a series of proteolytic cleavages that lead to the release either of an amyloidogenic fragment called beta-amyloid (A beta) or of a nonamyloidogenic secreted form consisting of the ectodomain of APP (APP(sec)). It is A beta that accumulates in the brain lesions that are thought to cause the disease. By reducing the cellular cholesterol level of living hippocampal neurons by 70% with lovastatin and methyl-beta-cyclodextrin, we show that the formation of AP is completely inhibited while the generation of APP(sec) is unperturbed. This inhibition of A beta formation is accompanied by increased solubility in the detergent Triton X-100 and is fully reversible by the readdition of cholesterol to previously depleted cells. Our results show that cholesterol is required for A beta formation to occur and imply a link between cholesterol, A beta, and Alzheimer's disease.
引用
收藏
页码：6460 / 6464
页数：5
相关论文
共 32 条
[1]   MEVINOLIN - A HIGHLY POTENT COMPETITIVE INHIBITOR OF HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE AND A CHOLESTEROL-LOWERING AGENT [J].
ALBERTS, AW ;
CHEN, J ;
KURON, G ;
HUNT, V ;
HUFF, J ;
HOFFMAN, C ;
ROTHROCK, J ;
LOPEZ, M ;
JOSHUA, H ;
HARRIS, E ;
PATCHETT, A ;
MONAGHAN, R ;
CURRIE, S ;
STAPLEY, E ;
ALBERSSCHONBERG, G ;
HENSENS, O ;
HIRSHFIELD, J ;
HOOGSTEEN, K ;
LIESCH, J ;
SPRINGER, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (07) :3957-3961
[2]   Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like properties [J].
Bouillot, C ;
Prochiantz, A ;
Rougon, G ;
Allinquant, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (13) :7640-7644
[3]   SORTING OF GPI-ANCHORED PROTEINS TO GLYCOLIPID-ENRICHED MEMBRANE SUBDOMAINS DURING TRANSPORT TO THE APICAL CELL-SURFACE [J].
BROWN, DA ;
ROSE, JK .
CELL, 1992, 68 (03) :533-544
[4]  
CERNEUS DP, 1993, J BIOL CHEM, V268, P3150
[5]   PRODUCTION OF INTRACELLULAR AMYLOID-CONTAINING FRAGMENTS IN HIPPOCAMPAL-NEURONS EXPRESSING HUMAN AMYLOID PRECURSOR PROTEIN AND PROTECTION AGAINST AMYLOIDOGENESIS BY SUBTLE AMINO-ACID SUBSTITUTIONS IN THE RODENT SEQUENCE [J].
DESTROOPER, B ;
SIMONS, M ;
MULTHAUP, G ;
VANLEUVEN, F ;
BEYREUTHER, K ;
DOTTI, CG .
EMBO JOURNAL, 1995, 14 (20) :4932-4938
[6]   GLYCOSPHINGOLIPID-ENRICHED, DETERGENT-INSOLUBLE COMPLEXES IN PROTEIN SORTING IN EPITHELIAL-CELLS [J].
FIEDLER, K ;
KOBAYASHI, T ;
KURZCHALIA, TV ;
SIMONS, K .
BIOCHEMISTRY, 1993, 32 (25) :6365-6373
[7]  
Goslin K., 1991, CULTURING NERVE CELL, P251
[8]   CELLULAR PROCESSING OF BETA-AMYLOID PRECURSOR PROTEIN AND THE GENESIS OF AMYLOID BETA-PEPTIDE [J].
HAASS, C ;
SELKOE, DJ .
CELL, 1993, 75 (06) :1039-1042
[9]   INHIBITION OF BETA-AMYLOID FORMATION IDENTIFIES PROTEOLYTIC PRECURSORS AND SUBCELLULAR SITE OF CATABOLISM [J].
HIGAKI, J ;
QUON, D ;
ZHONG, ZY ;
CORDELL, B .
NEURON, 1995, 14 (03) :651-659
[10]   Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study [J].
Hofman, A ;
Ott, A ;
Breteler, MMB ;
Bots, ML ;
Slooter, AJC ;
vanHarskamp, F ;
vanDuijn, CN ;
Van Broeckhoven, C ;
Grobbee, DE .
LANCET, 1997, 349 (9046) :151-154
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