title: Amyloid β-peptide 25-35 self-assembly and its inhibition: a model undecapeptide system to gain atomistic and secondary structure details of the Alzheimer's disease process and treatment.
abstract: Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the β-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid β-peptide 25-35 [Aβ(25-35)]. Aβ(25-35) was chosen because it is the shortest fragment capable of forming large β-sheet fibrils and retaining the toxicity of the full length Aβ(1-40/42) peptides. The conformational transition, that leads to the formation of β-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker Aβ(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Aβ(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Naldi
authors.forename: Jessica
authors.initials: J
authors.lastname: Fiori
authors.forename: Marco
authors.initials: M
authors.lastname: Pistolozzi
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
authors.forename: Rongliang
authors.initials: R
authors.lastname: Wu
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mlynarczyk
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D002942:Circular Dichroism / Q000379:methods; D003474:Curcumin / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008958:Models, Molecular; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence / Q000379:methods; D013696:Temperature; D013752:Tetracycline / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D005419:Flavonoids; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C040015:myricetin; D013752:Tetracycline; D003474:Curcumin