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 - PubMed (original) (raw)
. 2013 Nov 13;135(45):16926-37.
doi: 10.1021/ja406197f. Epub 2013 Nov 1.
Affiliations
- PMID: 24131107
- DOI: 10.1021/ja406197f
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
Christian Bleiholder et al. J Am Chem Soc. 2013.
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.
Similar articles
- Understanding amyloid fibril nucleation and aβ oligomer/drug interactions from computer simulations.
Nguyen P, Derreumaux P. Nguyen P, et al. Acc Chem Res. 2014 Feb 18;47(2):603-11. doi: 10.1021/ar4002075. Epub 2013 Dec 24. Acc Chem Res. 2014. PMID: 24368046 Review. - Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01.
Sinha S, Du Z, Maiti P, Klärner FG, Schrader T, Wang C, Bitan G. Sinha S, et al. ACS Chem Neurosci. 2012 Jun 20;3(6):451-8. doi: 10.1021/cn200133x. Epub 2012 Mar 7. ACS Chem Neurosci. 2012. PMID: 22860214 Free PMC article. - Ion mobility-mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation.
Bleiholder C, Dupuis NF, Wyttenbach T, Bowers MT. Bleiholder C, et al. Nat Chem. 2011 Feb;3(2):172-7. doi: 10.1038/nchem.945. Epub 2010 Dec 19. Nat Chem. 2011. PMID: 21258392 Free PMC article. - Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease.
Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J. Hawkes CA, et al. Eur J Neurosci. 2010 Jan;31(2):203-13. doi: 10.1111/j.1460-9568.2009.07052.x. Epub 2010 Jan 13. Eur J Neurosci. 2010. PMID: 20074226 - A solution NMR toolset to probe the molecular mechanisms of amyloid inhibitors.
Ahmed R , Melacini G . Ahmed R , et al. Chem Commun (Camb). 2018 May 3;54(37):4644-4652. doi: 10.1039/c8cc01380b. Chem Commun (Camb). 2018. PMID: 29658548 Review.
Cited by
- On the Preservation of Non-covalent Peptide Assemblies in a Tandem-Trapped Ion Mobility Spectrometer-Mass Spectrometer (TIMS-TIMS-MS).
Kirk SR, Liu FC, Cropley TC, Carlock HR, Bleiholder C. Kirk SR, et al. J Am Soc Mass Spectrom. 2019 Jul;30(7):1204-1212. doi: 10.1007/s13361-019-02200-y. Epub 2019 Apr 25. J Am Soc Mass Spectrom. 2019. PMID: 31025294 - Ion mobility spectrometry: A personal view of its development at UCSB.
Bowers MT. Bowers MT. Int J Mass Spectrom. 2014 Sep 15;370:75-95. doi: 10.1016/j.ijms.2014.06.016. Int J Mass Spectrom. 2014. PMID: 25147478 Free PMC article. - Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer's Disease.
Downey MA, Giammona MJ, Lang CA, Buratto SK, Singh A, Bowers MT. Downey MA, et al. J Am Soc Mass Spectrom. 2019 Jan;30(1):85-93. doi: 10.1007/s13361-018-1975-1. Epub 2018 Apr 30. J Am Soc Mass Spectrom. 2019. PMID: 29713966 Free PMC article. - Opposing Effects of Cucurbit[7]uril and 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose on Amyloid β25-35 Assembly.
de Almeida NE, Do TD, Tro M, LaPointe NE, Feinstein SC, Shea JE, Bowers MT. de Almeida NE, et al. ACS Chem Neurosci. 2016 Feb 17;7(2):218-26. doi: 10.1021/acschemneuro.5b00280. Epub 2015 Dec 10. ACS Chem Neurosci. 2016. PMID: 26629788 Free PMC article. - "Wet" Versus "Dry" Folding of Polyproline.
Shi L, Holliday AE, Bohrer BC, Kim D, Servage KA, Russell DH, Clemmer DE. Shi L, et al. J Am Soc Mass Spectrom. 2016 Jun;27(6):1037-47. doi: 10.1007/s13361-016-1372-6. Epub 2016 Apr 8. J Am Soc Mass Spectrom. 2016. PMID: 27059978 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources