Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies

• Published in: PloS one 2012-04, Vol.7 (4), p.e35807
• Main Authors: Chen, Wei-Ting, Hong, Chen-Jee, Lin, Ya-Tzu, Chang, Wen-Han, Huang, He-Ting, Liao, Jhih-Ying, Chang, Yu-Jen, Hsieh, Yi-Fang, Cheng, Chih-Ya, Liu, Hsiu-Chih, Chen, Yun-Ru, Cheng, Irene H
• Format: Article
• Language: English
• Subjects: Agglomeration; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Aspartic Acid - chemistry; Aspartic Acid - genetics; Base Sequence; Biochemical analysis; Biochemistry; Biology; Brain research; Cells, Cultured; Cellular manufacture; Clinical medicine; Copper; Copper - chemistry; Copper - metabolism; Etiology; Female; Genomics; HEK293 Cells; Histidine; Histidine - chemistry; Histidine - genetics; Humans; Low molecular weights; Medicine; Middle Aged; Molecular Sequence Data; Molecular weight; Mutation; Neurodegenerative diseases; Neurotoxicity; Oligomerization; Oligomers; Pathogenicity; Pathogens; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptides; Physics; Polymerization; Science; Studies; Taiwan; Zinc; Zinc - chemistry; Zinc - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035807

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.