Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts.
Formation of senile plaques containing the beta-amyloid peptide (A beta) 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 A beta) 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 A beta generation. Reducing cholesterol levels in N2a cells decreased A beta 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 A beta in a cholesterol-dependent manner. A beta generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-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 A beta generation, may be determined by dynamic interactions of APP with lipid rafts.
Ehehalt
Robert
R
Max Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden, Germany.
Keller
Patrick
P
Haass
Christian
C
Thiele
Christoph
C
Simons
Kai
K
D000256:Adenoviridae / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001710:Biotin / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004705:Endocytosis; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D011233:Precipitin Tests; D011990:Receptors, Transferrin / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D003432:Cross-Linking Reagents; D003902:Detergents; D011990:Receptors, Transferrin; D014168:Transferrin; D001710:Biotin; D002784:Cholesterol; D000469:Alkaline Phosphatase