J Am Chem Soc. 2013 Nov 13;135(45):16926-37. doi: 10.1021/ja406197f. Epub 2013 Nov 1.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.
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