Amyloid-beta (A?) D7H mutation increases oligomeric A?42 and alters properties of A?-zinc/copper assemblies.

ABSTRACT: Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid ?-protein (A?) levels or aggregation. Here, we identified a novel APP mutation, located within the A? sequence (A?(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? production, A?42/40 ratio and prolonged A?42 oligomer state with higher neurotoxicity. Because the D7H mutant A? has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of A? to ion. When co-incubated with Zn(2+) or Cu(2+), A?(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? production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the A? N-terminal region potentially modulates APP processing and A? aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.

SUBMITTER: Chen WT 

PROVIDER: S-EPMC3340413 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature