The amyloid beta protein precursor mutations linked to familial Alzheimer's disease alter processing in a way that fosters amyloid deposition.
Normal processing of the amyloid beta protein precursor (BAPP) results in secretion of a soluble 4 kD protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease (AD). Strong evidence that amyloid deposition plays a critical role in the development of AD has come from the identification of familial AD (FAD) kindreds in which the AD phenotype cosegregates with mutations in the beta APP gene that are located close to the NH2 or COOH end of the A beta peptide. The location of these mutations immediately suggests that they may cause AD by altering beta APP processing in a way that is amyloidogenic. In a previous study, we found that transfected cells expressing the NH2 side mutant secrete 6-fold more 4 kD A beta than those expressing wild type beta APP or COOH side mutants. We have now shown that the mutations on the COOH side of A beta alter processing to increase secretion of the more amyloidogenic A beta 1-42 form which constitutes only a small percentage of the total 4 kD A beta produced. Thus our data show that all of the FAD-linked beta APP mutations alter beta APP processing in a way that increases the likelihood of amyloid formation.
Younkin
S G
SG
Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio, USA.
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D004314:Down Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human