Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer’s disease related oligomers

eLife

Harald Schwalbe¹  Elke Stirnal¹  Marie J Hutchison¹  Tina Stark¹  Nina Morgner²  Janosch Martin²  Jan Hoffmann²  Tobias Lieblein²  Rene Zangl²  Thomas Schrader³ 

[1] JW Goethe-University, Institute for Organic Chemistry and Chemical Biology and Center for Biomolecular Magnetic Resonance, Frankfurt am Main, Germany;JW Goethe-University, Institute of Physical and Theoretical Chemistry, Frankfurt, Germany;University of Duisburg-Essen, Institute of Organic Chemistry, Essen, Germany;

关键词: amyloid beta-peptides;    mass spectrometry;    aggregation;    conformation analysis;    ion mobility spectrometry;   

DOI  :  10.7554/eLife.59306

来源: DOAJ

【 摘 要 】

The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular, we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here, we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.

【 授权许可】

Unknown