Amyloid-Beta D7H Mutation Increases Oligomeric A[beta]42 and Alters Properties of A[beta]-Zinc/Copper Assemblies

Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid [beta]-protein (A[beta]) levels or aggregation. Here, we identified a novel APP mutation, located within the A[beta] sequence (A[beta].sub.D7H ), in a Taiwanese famil...

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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:
Advertising executives
Alzheimer's disease
Amyloid beta-protein
Analysis
Development and progression
Genetic aspects
Histidine
Oligomers
Zinc compounds
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Summary:Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid [beta]-protein (A[beta]) levels or aggregation. Here, we identified a novel APP mutation, located within the A[beta] sequence (A[beta].sub.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 A[beta] production, A[beta]42/40 ratio and prolonged A[beta]42 oligomer state with higher neurotoxicity. Because the D7H mutant A[beta] has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of A[beta] to ion. When co-incubated with Zn.sup.2+ or Cu.sup.2+, A[beta].sub.D7H aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both A[beta] production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the A[beta] N-terminal region potentially modulates APP processing and A[beta] aggregation, and further provides a genetic indication of the importance of Zn.sup.2+ and Cu.sup.2+ in the etiology of AD.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0035807