The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.
Several missense mutations causing early-onset Alzheimer's disease (AD) have been described in the gene coding for the beta-amyloid precursor protein (beta APP). A double mutation found in a Swedish family is located before the amyloid beta-peptide (A beta) region of beta APP and results in the increased production and secretion of A beta. Here we show that the increased production of A beta results from a cellular mechanism, which differs substantially from that responsible for the production of A beta from wild-type beta APP. In the latter case, A beta generation requires reinternalization and recycling of beta APP. In the case of the Swedish mutation the N-terminal beta-secretase cleavage of A beta occurs in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurs in the same compartment as the alpha-secretase cleavage, which normally prevents A beta production, explaining the increased A beta generation by a competition between alpha- and beta-secretase.
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013548:Sweden
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human