title: An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.
abstract: Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate A beta 1-40 from the longer A beta 1-42. Both methods demonstrated that the 4-kilodalton A beta released from wild-type beta APP is primarily but not exclusively A beta 1-40. The beta APP717 mutations, which are located three residues carboxyl to A beta 43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta 1-42) forms insoluble amyloid fibrils more rapidly than A beta 1-40. Thus, the beta APP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.
authors.affiliation: Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: T T
authors.initials: TT
authors.lastname: Cheung
authors.forename: X D
authors.initials: XD
authors.lastname: Cai
authors.forename: A
authors.initials: A
authors.lastname: Odaka
authors.forename: L
authors.initials: L
authors.lastname: Otvos
authors.forename: C
authors.initials: C
authors.lastname: Eckman
authors.forename: T E
authors.initials: TE
authors.lastname: Golde
authors.forename: S G
authors.initials: SG
authors.lastname: Younkin
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C094559:APP717; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned