Alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease.
Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familial forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PS1 mutations clearly trigger an increased production of the 42-amino-acid-long species of beta-amyloid peptide (A beta). Here we show that overexpression of wild-type PS1 in HK293 cells increases A beta40 secretion. By contrast, FAD-linked mutants of PS1 trigger increased secretion of both A beta40 and A beta42 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PS1 augments the alpha-secretase-derived C-terminally truncated fragment of beta-amyloid precursor protein (APP alpha) recovery, whereas transfectants expressing mutated PS1 secrete drastically lower amounts of APP alpha when compared with cells expressing wild-type PS1. This decrease was also observed when comparing double transfectants overexpressing wild-type beta-amyloid precursor protein and either PS1 or its mutated congener M146V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of A beta42 over total A beta secretion but concomitantly down-regulate the production of APP alpha.
Ancolio
K
K
Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France.
Marambaud
P
P
Dauch
P
P
Checler
F
F
D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human