title: Overexpression of amyloid precursor protein alters its normal processing and is associated with neurotoxicity.
abstract: The recent discovery that point mutations in the beta/A4 amyloid precursor protein may be the cause of certain forms of familial Alzheimer's disease provides strong support for the view that a thorough understanding of the metabolism of this protein may elucidate the pathogenesis of most forms of the disease and thus serve as a basis for rational prevention and therapy. Here we show that overexpression of a portion of the amyloid precursor protein molecule produces at least four distinct fragments of the COOH-terminus of amyloid precursor protein, suggesting altered proteolysis of amyloid precursor protein, and that such overexpression is associated with cytotoxicity. The degree of toxicity in the P19 cell culture model (differentiating mouse embryonal carcinoma cells) is shown to be related to the two larger novel COOH-terminal protein fragments (16 and 14 kilodalton), as well as to levels of expression of these two fragments. The toxicity is manifested in several differentiated cell lineages, including neuronal cells.
authors.affiliation: Department of Pathology SM-30, University of Washington, Seattle 98195.
authors.forename: K
authors.initials: K
authors.lastname: Fukuchi
authors.forename: K
authors.initials: K
authors.lastname: Kamino
authors.forename: S S
authors.initials: SS
authors.lastname: Deeb
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Dang
authors.forename: G M
authors.initials: GM
authors.lastname: Martin
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D007700:Kinetics; D009498:Neurotoxins; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D015183:Restriction Mapping; D013997:Time Factors; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D009498:Neurotoxins