Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

被引:892
作者
Ehehalt, R
Keller, P
Haass, C
Thiele, C
Simons, K
机构
[1] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany
[2] Univ Munich, Adolf Butenandt Inst, Dept Biochem, Lab Alzheimers & Parkinsons Dis Res, D-80336 Munich, Germany
关键词
lipid rafts; beta-amyloid; BACE; Alzheimer's disease; endocytosis;
D O I
10.1083/jcb.200207113
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Formation of senile plaques containing the beta-amyloid peptide (Abeta) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by beta-secretase or by alpha-secretase to initiate amyloidogenic (release of Abeta) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Abeta generation. Reducing cholesterol levels in N2a cells decreased Abeta production. APP and the beta-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Abeta in a cholesterol-dependent manner. Abeta generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTP se-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by beta-secretase, APP outside rafts undergoes cleavage by alpha-secretase. Thus, access of alpha- and beta-secretase to APP, and therefore Abeta generation, may be determined by dynamic interactions of APP with lipid rafts.
引用
收藏
页码:113 / 123
页数:11
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