Assessment of an Initial Roadmap for Protein-Protein-Small Molecule Networks in the Brain of Alzheimer’s Disease
[摘要] Alzheimer’s disease (AD) is one of the fatal and leading causes of death. Amyloid-beta (Abeta) and transition metal ions [which can bind each other and may influence peptide aggregation, producing toxic oligomeric Abeta species, and reactive oxygen species (ROS)] have been suggested to be involved in AD pathogenesis. In addition, there may be interactions of Abeta with other proteins [i.e., human serum albumin (HSA), S100 proteins]. Unfortunately, a clear relationship between Abeta, metal ions, and other proteins in AD etiology has not been identified. In order to understand the role of metal-associated Abeta (metal–Abeta) species in AD, several chemical tools have been studied and presented their abilities toward A-beta. The structural moieties responsible for such reactivities, however, are not completely elucidated. To gain a better understanding of structure-interaction-reactivity relationships between small molecules and metal-free Abeta or metal–Abeta, naturally occurring flavonoids (morin, quercetin, galangin, and luteolin) with structural variations (i.e., the number and position of hydroxyl functionality) and two series of rationally designed chemical reagents were investigated. Four flavonoids in this study could significantly modulate aggregation pathways of metal–Abeta over metal-free Abeta and mediate Abeta-linked cytotoxicity to different extents. The variations of hydroxyl groups within a flavonoid backbone can modify their reactivity toward Abeta species. In addition, the motif of N1,N1-dimethylbenzene-1,4-diamine could be considered to be essential for targeting and modulating Abeta aggregation pathways and scavenging free radicals. Moreover, we have examined the interactions of Abeta with other proteins (i.e., HSA, S100 proteins) with and without metal ions and their influence on the peptide aggregation. HSA and S100 proteins could alter the Abeta aggregation pathways by directly binding to Abeta followed by formation of complexes which possibly are less toxic than protein-free Abeta aggregates. Taken together, the studies described in this thesis demonstrate the pivotal functionalities of chemical tools for their reactivity toward metal-free and metal-bound Abeta, as well as present the initial information on a link of protein–protein–small molecule (metal) networks to AD etiology. Our overall results and observations will be able to provide insight into new discovery of chemical tools and therapeutics toward AD.
[发布日期] [发布机构] University of Michigan
[效力级别] s disease [学科分类]
[关键词] Alzheimer"s disease;amyloid;metal ions;human serum albumin;S100;Chemistry;Science;Chemistry [时效性]