Affiliations: [a]
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia | [b]
Orekhovich Institute of Biomedical Chemistry, Moscow, Russia | [c] Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
Correspondence:
[*]
Correspondence to: Sergey P. Radko, Engelhardt Institute of Molecular Biology, Vavilova Str. 32, Moscow 119991, Russia. Tel.: +7 499 1352311; Fax: +7 499 1351405; E-mail: radkos@yandex.ru.
Abstract: Zinc-induced aggregation of amyloid-β peptides (Aβ) is considered to contribute to the pathogenesis of Alzheimer’s disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aβ self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous Aβ aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aβ42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aβ16 peptides to model the Aβ metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aβ42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aβ42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aβ42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aβ16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aβ aggregation.
