ESI-MS Identification of the Minimal Zinc-Binding Center in Natural Isoforms of β-Amyloid Domain 1-16

Alzheimer's disease is a lethal neurodegenerative pathology accompanied by the formation of water-soluble neurotoxic oligomers of the human beta-amyloid peptide, A beta, which are then accumulated as polymeric extracellular aggregates (the so-called amyloid plaques). The human A beta isoform isomerized at aspartate 7 (isoA beta) 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 beta-amyloid (Tottori mutation) has been proposed. However, the rat/mouse A beta (ratA beta), 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 A beta isoforms. The interactions with zinc ion play a key role in the in vitro and in vivo aggregation of monomeric human A beta. Here, we have used high-resolution ESI-MS to demonstrate for the first time that domains 1-16 of the isoforms isoA beta and D7N-A beta bind zinc ion in exactly the same manner as human 1-16 A beta domain. On the other hand, the structure of the minimal zinc-binding center in ratA beta differs significantly. These results confirm the general mechanism underlying the interaction of zinc ions with human A beta isoforms and suggest that structural modulations of A beta region 6-14 can be used as a promising approach to the therapy of Alzheimer's disease.