Amyloid precursor-like protein 1 influences endocytosis and proteolytic processing of the amyloid precursor protein.
Ectodomain shedding of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer disease amyloid beta peptide (Abeta). The molecular mechanisms underlying the control of APP shedding remain little understood but are in part dependent on the low density lipoprotein receptor-related protein (LRP), which is involved in APP endocytosis. Here, we show that the APP homolog APLP1 (amyloid precursor-like protein 1) influences APP shedding. In human embryonic kidney 293 cells expression of APLP1 strongly activated APP shedding by alpha-secretase and slightly reduced beta-secretase cleavage. As revealed by domain deletion analysis, the increase in APP shedding required the NPTY amino acid motif within the cytoplasmic domain of APLP1. This motif is conserved in APP and is essential for the endocytosis of APP and APLP1. Unrelated membrane proteins containing similar endocytic motifs did not affect APP shedding, showing that the increase in APP shedding was specific to APLP1. In LRP-deficient cells APLP1 no longer induced APP shedding, suggesting that in wild-type cells APLP1 interferes with the LRP-dependent endocytosis of APP and there by increases APP alpha-cleavage. In fact, an antibody uptake assay revealed that expression of APLP1 reduced the rate of APP endocytosis. In summary, our study provides a novel mechanism for APP shedding, in which APLP1 affects the endocytosis of APP and makes more APP available for alpha-secretase cleavage.
Neumann
Stephanie
S
Adolf-Butenandt-Institut, Ludwig-Maximilians-University, Schillerstrasse 44, 80336 Munich, Germany.
Schöbel
Susanne
S
Jäger
Sebastian
S
Trautwein
Anna
A
Haass
Christian
C
Pietrzik
Claus U
CU
Lichtenthaler
Stefan F
SF
D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human