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 (AβD7H), 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 Zn2+ or Cu2+, AβD7H 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 Zn2+ and Cu2+ in the etiology of AD.

Alzheimer’s amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity

“…The identified mutations inside Aβ region are mainly located at the N-terminus or in the middle region within residues 21 to 23. They are English (H6R)[22], Tottori (D7N)[22, 23], Taiwan (D7H)[24], Flemish (A21G)[25], Arctic (E22G)[26], Dutch (E22Q)[27, 28], Italian (E22K)[29], and Iowa (D23N)[30]. Recently, genetic variation found in normal people and patients with FAD has revealed an important role for the very N-terminus of Aβ for risk of AD[22, 31–33].…”

Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer’s Disease Mutation

“…However, as with the central region of Aβ, a number of APP mutations result in amino acid substitutions at the N-terminus, and these substitutions alter Aβ assembly. These include the English (H6R) 26-27 , Tottori (D7N) 26-29 , and Taiwanese (D7H) 30 mutations. The importance of the Aβ N-terminus in disease causation thus is clear.…”

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

“…Initially, it was thought that Zn 2+ promoted formation of off-pathway, amorphous aggregates [34][35][36][37][38][39]; however, it has also been reported that Zn 2+ can cause Aβ to form annular protofibrils [40,41]. Zn 2+ is thought to induce Aβ to rapidly form disc shaped oligomers that are highly toxic to primary cell culture, but may then further aggregate to form non-toxic assemblies [42].…”