Abstract
One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-epigallocatechin-3-gallate, quercetin, and rosmarinic acid) with amyloid-β(1–40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.
Highlights
The pathological hallmark of Alzheimer’s disease (AD) is the extracellular accumulation of insoluble proteinaceous deposits called amyloid fibrils [1] that induce cytotoxicity
Epidemiological studies on the effects of the diet against AD and dementia suggested that the high intake of flavonoids and polyphenols found in fruits and vegetables reduces the risk of AD and cognitive impairments, and several natural molecules have been identified as promoting cognitive health and interfering with the amyloidogenic activity in AD [4]
The replica exchange molecular dynamics (REMD) methodology used does not allow the biophenols to enter into the hydrophobic core of the preformed protofibril, probably because the energy penalty associated with the penetration process cannot be overcome using conventional molecular dynamics (MD)
Summary
The pathological hallmark of Alzheimer’s disease (AD) is the extracellular accumulation of insoluble proteinaceous deposits called amyloid fibrils [1] that induce cytotoxicity. The formation of mature amyloid fibrils (Aβ) proceeds through a nucleation-dependent process, where monomers and oligomers aggregate together, forming β-sheet-rich protein structures. Destabilization and clearance of amyloid aggregates by small molecules is one of the promising approaches towards the development of AD therapies [3]. Epidemiological studies on the effects of the diet against AD and dementia suggested that the high intake of flavonoids and polyphenols found in fruits and vegetables reduces the risk of AD and cognitive impairments, and several natural molecules have been identified as promoting cognitive health and interfering with the amyloidogenic activity in AD [4]. Despite intensive research, the experimental characterization of full-length Aβ oligomers/inhibitor complexes at a high level of resolution remains a great challenge
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