Mechanistic and Structural Insights into the Chemical Modulation of Amyloid Aggregation

Protein Aggregation;Amyloids;Alzheimer"s disease;Biological Chemistry;Chemistry;Science;Chemistry

Korshavn, KyleRuotolo, Brandon Thomas ;

University of Michigan

关键词: Protein Aggregation;    Amyloids;    Alzheimer";    s disease;    Biological Chemistry;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/137139/kkorshav_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The aggregation of amyloid-beta (Abeta) is implicated in the etiology of Alzheimer’s disease (AD). Aggregation in vivo permits interactions with transition metal ions and lipids of the cell membrane. Abeta-metal interactions are suggested to induce metal ion dyshomeostasis and promote oxidative stress while Abeta-membrane interactions catalyze the formation of specific oligomers which destabilize and permeabilize the lipid bilayer. Oxidative stress may also modulate bilayer integrity through acyl chain peroxidation which causes membrane thinning. The structural and mechanistic effects of these interactions on the aggregation of Abeta remain unclear. Multiple glycosidic polyphenol natural products and their esterified derivatives were investigated for their ability to function as molecular probes against metal-Abeta. The interactions between Abeta and thin model membranes were also investigated through a combination of NMR spectroscopy, fluorescence spectroscopy, and atomic force and transmission electron microscopies.The natural products Phlorizin, Verbascoside, and Rutin were all evaluated for their ability to modulate metal-Abeta aggregation. Verbascoside effectively inhibited aggregation while its esterified derivative, VPP, showed similar efficacy in vitro. Both compounds were also capable of disaggregating preformed fibrils, though they bound to both the monomeric and fibrillar forms of Abeta through distinct mechanisms. Esterification greatly reduced VPP’s ability to inhibit metal-Abeta cytotoxicity, however.Subsequently, the interaction and aggregation of Abeta with both thick (DOPC or POPC) and thin (DLPC) model membranes was evaluated. tr-NOESY and relaxation based NMR experiments probed monomer interaction on the bilayer surface; folding was conserved regardless of bilayer thickness, suggesting that the preliminary interaction is exclusively driven by surface contacts. Additionally, the work provides the first experimentally derived structural constraints for membrane-associated Abeta. The progression of Abeta from its conserved, folded, monomeric state to its aggregated state was monitored in the presence of thick and thin membranes. DLPC bilayers uniquely stabilized membrane associated oligomers while simultaneously destabilizing the bilayer. DLPC also remodeled preformed fibrils into a pseudo-unfolded state which resembles protofibrillar aggregates. These results provide a new reagent with potential applications as a probe against metal-Abeta in vitro and insights into early structures of membrane-associated Abeta and mechanisms by which membrane structure can modulate the Abeta aggregation.