title: Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies.
abstract: Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (Aβ(D7H)), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn(2+) or Cu(2+), Aβ(D7H) aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.
authors.affiliation: Institute of Brain Science, National Yang Ming University, Taipei, Taiwan.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Chen
authors.forename: Chen-Jee
authors.initials: CJ
authors.lastname: Hong
authors.forename: Ya-Tzu
authors.initials: YT
authors.lastname: Lin
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Chang
authors.forename: He-Ting
authors.initials: HT
authors.lastname: Huang
authors.forename: Jhih-Ying
authors.initials: JY
authors.lastname: Liao
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chang
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Hsieh
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Cheng
authors.forename: Hsiu-Chih
authors.initials: HC
authors.lastname: Liu
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.forename: Irene H
authors.initials: IH
authors.lastname: Cheng
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics*; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006639:Histidine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D058105:Polymerization; D013624:Taiwan; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D001224:Aspartic Acid; D006639:Histidine; D003300:Copper; D015032:Zinc