Amyloid-Beta (Aβ) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-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(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 Zn2+ or Cu2+, A beta(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 Zn2+ and Cu2+ in the etiology of AD.