N-TRUNCATED AND PYROGLUTAMATE-MODIFIED Aβ ACCELERATES AGGREGATION OF α-SYNUCLEIN IN VITRO

Abstract

The aggregation and depositoion of misfolded α-synuclein and Aβ represent hallmarks of Parkinson's and Alzheimer's disease, respectively. Interestingly, α-synuclein and Aβ pathology are frequently observed in the same individual, leading to the hypothesis that both peptides mutually interact to facilitate neurodegeneration. Here, we studied the influence of Aβ1–42 and pGlu-Aβ3–42 on the aggregation of α-synuclein in vitro. Human alpha-synuclein was recombinantly expressed in Escherichia coli and purified. Aβ1–42 and pGlu- Aβ3–42 were synthesized by solid phase synthesis. The aggregation of alpha-synuclein was investigated using Thioflavin-T fluorescence assay, atomic force (AFM) and transmission electron microscopy (TEM). We observed a significantly increased aggregation velocity of α-synuclein in presence of Aβ1–42 and pGlu-Aβ3–42. Notably, the effect was already obvious if the concentration of Aβ was 75fold below the concentration of α-synuclein. An analysis of the structure of the fibrils by AFM and TEM did not reveal structural changes upon seeding by Aβ. Our results suggest an interaction of α-synuclein and Aβ in vitro, leading to an accelerated fibril formation. We hypothesize that the effect is caused by an enhanced nucleus formation. These observations might have implications for a potential cross-talk of amyloid peptides in neurodegeneration.