Jana Rüdel, Maria Ott
Institute of Physics, Martin-Luther-University Halle-Wittenberg
Similar to synthetic polymers like polyamides, amyloidogenic proteins as well as short peptide sequences display the inherent ability to form long and very stable fibers called fibrils. Along the pathway from a single peptide to the mature fibrils, various transient and long-lived intermediate states are formed spanning the whole range between small and mostly unstructured oligomers to well-ordered, β-sheet rich protofibrils. As early oligomeric states were found to be neurotoxic, they are a presumptive key to understand the development of neurodegenerative diseases [1].
In order to reveal the leading mechanisms of amyloid aggregation, we studied the appearance and development of early oligomeric states of the Aβ40- and the Aβ42-peptides using a combined approach of single-molecule fluorescence spectroscopy and imaging techniques, such as TEM and AFM. Additionally, thermodynamic stabilities of the detected amyloid aggregates were studied by the use of ultrafast-scanning calorimetry.
We could reveal and characterize soluble oligomers of the Aβ40- and the Aβ42-peptide and found distinct differences in terms of size distribution as well as the process of oligomerization. While the fibrillation of Aβ42-peptides includes small and large oligomers, the assembly of Aβ40-peptide display only small oligomers and an overall slower kinetic of fibril formation. We will discuss our results by the use of thermodynamic models of self-assembly.
References
[1] F. Bemporad and F. Chiti, Protein misfolded oligomers: Experimental approaches, mechanism of formation, and structure-toxicity relationships, Chem. Biol. 19 (2012), 315 (link)