ИСТИНА

Alzheimer's disease is an increasingly familiar neurodegenerative disease that ultimately leads to dementia and death. According to the amyloid hypothesis, which has been the predominant framework for Alzheimer disease (AD) studies, amyloid-β peptide (Aβ) aggregation has a unique and critical role as an initiator of AD pathology. Conformational changes of Aβ peptide result in its transformation from native monomeric state to the toxic soluble dimers, oligomers and insoluble aggregates that are hallmarks of AD. Interactions of zinc ions with Aβ are mediated by the N-terminal Aβ1-16 domain and appear to play a key role in AD progression. There is a range of results indicating that these interactions trigger the Aβ plaque formation. We have used high resolution NMR spectroscopy to reveal the structural determinants of zinc-induced Aβ oligomerization, i.e. the structure elements that are responsible for the ability of Aβ to form zinc-bound intermolecular complexes. Synthetic peptides corresponding to the metal binding domains of the intact Aβ, of the English H6R Aβ mutant, Aβ containing age-related isomerized D7 residue and several truncated and mutant forms of these peptides have been used as experimental models. We have determined structure and functional characteristics of the metal binding domains derived from several Aβ variants and found that their zinc-induced oligomerization is governed by conformational changes in the minimal zinc binding site 6HDSGYEVHH14 [1-3]. The residue H6 and segment 11EVHH14, which are part of this site, are crucial for formation of the two zinc-mediated interaction interfaces in Aβ. Taken together, the data indicate that interplay of histidine residues in the minimal zinc-binding site 6-14 of Aβ upon its interactions with zinc ions underlies critical conformational changes of Aβ, which in turn lead to Aβ dimerization, oligomerization and aggregation. The results provide structural basis for rational design of the AD-modifying drugs aimed at blocking pathological Aβ aggregation.