title: Ion mobility spectrometry reveals the mechanism of amyloid formation of Aβ(25-35) and its modulation by inhibitors at the molecular level: epigallocatechin gallate and scyllo-inositol.
abstract: Amyloid cascades leading to peptide β-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with the cellular machinery. The relationship between the transformation from natively unstructured assembly to the β-sheet oligomers to disease is important in understanding disease onset and the development of therapeutic agents. Research on this early oligomeric region has largely been unsuccessful since traditional techniques measure only ensemble average oligomer properties. Here, ion mobility methods are utilized to deduce the modulation of peptide self-assembly pathways in the amyloid-β protein fragment Aβ(25-35) by two amyloid inhibitors (epigallocatechin gallate and scyllo-inositol) that are currently in clinical trials for Alzheimer's Disease. We provide evidence that suppression of β-extended oligomers from the onset of the conversion into β-oligomer conformations is essential for effective attenuation of β-structured amyloid oligomeric species often associated with oligomer toxicity. Furthermore, we demonstrate the ease with which ion mobility spectrometry-mass spectrometry can guide the development of therapeutic agents and drug evaluation by providing molecular level insight into the amyloid formation process and its modulation by small molecule assembly modulators.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106-9510, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Bleiholder
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Economou
authors.forename: Summer S
authors.initials: SS
authors.lastname: Bernstein
authors.forename: Steven K
authors.initials: SK
authors.lastname: Buratto
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007294:Inositol / Q000494:pharmacology*; D013058:Mass Spectrometry; D008958:Models, Molecular; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C009217:scyllitol; D007294:Inositol; D002392:Catechin; C045651:epigallocatechin gallate