JW Goethe-University, Institute of Physical and Theoretical Chemistry, Frankfurt, Germany.
JW Goethe-University, Institute for Organic Chemistry and Chemical Biology and Center for Biomolecular Magnetic Resonance, Frankfurt am Main, Germany.
Elife. 2020 Oct 23;9:e59306. doi: 10.7554/eLife.59306.
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.
寡聚体的形成淀粉样蛋白-β肽在阿尔茨海默病的发病机制中起着关键作用。本文通过质谱和离子淌度谱研究了与疾病相关的小淀粉样蛋白-β寡聚体，揭示了具有功能相关性的结构特征。特别是，我们可以证明淀粉样蛋白-β寡聚体以两种不同的方式形成，导致神经毒性寡聚体和纤维或非毒性无定形聚集体。在分子水平上理解导致这些途径的关键属性是特异性靶向该肽的三级结构的前提，目的是促进非毒性聚集体的出现。在这里，我们展示了两种纤维抑制配体，一种离子分子手性钳和一种疏水性肽，尽管它们的相互作用机制不同，但可以从第一个淀粉样蛋白-β寡聚体相应结构的消失来推断出纤维形成途径的抑制。
