ESI-MS identification of the minimal zinc-binding center in natural isoforms of β-amyloid domain 1–16

Abstract

Alzheimer’s disease is a lethal neurodegenerative pathology accompanied by the formation of water-soluble neurotoxic oligomers of the human β-amyloid peptide, Aβ, which are then accumulated as polymeric extracellular aggregates (the so-called amyloid plaques). The human Aβ isoform isomerized at aspartate 7 (isoAβ) is the major component of amyloid plaques and is regarded as a potential causative agent for Alzheimer’s disease. A mechanism for producing this isoform from a genetically determined variant of D7N β-amyloid (Tottori mutation) has been proposed. However, the rat/mouse Aβ (ratAβ), which carries three amino acid substitutions in metal-binding domain 1–16, is not susceptible to pathogenic aggregation in vivo, unlike the other known genetically determined or chemically modified natural Aβ isoforms. The interactions with zinc ion play a key role in the in vitro and in vivo aggregation of monomeric human Aβ. Here, we have used high-resolution ESI-MS to demonstrate for the first time that domains 1–16 of the isoforms isoAβ and D7N-Aβ bind zinc ion in exactly the same manner as human 1–16 Aβ domain. On the other hand, the structure of the minimal zinc-binding center in ratAβ differs significantly. These results confirm the general mechanism underlying the interaction of zinc ions with human Aβ isoforms and suggest that structural modulations of Aβ region 6–14 can be used as a promising approach to the therapy of Alzheimer’s disease.