Pyroglutamate-Modified Amyloid-?(3-42) Shows ?-Helical Intermediates before Amyloid Formation.

ABSTRACT: Pyroglutamate-modified amyloid-? (pEA?) has been described as a relevant A? species in Alzheimer's-disease-affected brains, with pEA? (3-42) as a dominant isoform. A? (1-40) and A? (1-42) have been well characterized under various solution conditions, including aqueous solutions containing trifluoroethanol (TFE). To characterize structural properties of pEA? (3-42) possibly underlying its drastically increased aggregation propensity compared to A? (1-42), we started our studies in various TFE-water mixtures and found striking differences between the two A? species. Soluble pEA? (3-42) has an increased tendency to form ?-sheet-rich structures compared to A? (1-42), as indicated by circular dichroism spectroscopy data. Kinetic assays monitored by thioflavin-T show drastically accelerated aggregation leading to large fibrils visualized by electron microscopy of pEA? (3-42) in contrast to A? (1-42). NMR spectroscopy was performed for backbone and side-chain chemical-shift assignments of monomeric pEA? (3-42) in 40% TFE solution. Although the difference between pEA? (3-42) and A? (1-42) is purely N-terminal, it has a significant impact on the chemical environment of >20% of the total amino acid residues, as revealed by their NMR chemical-shift differences. Freshly dissolved pEA? (3-42) contains two ?-helical regions connected by a flexible linker, whereas the N-terminus remains unstructured. We found that these ?-helices act as a transient intermediate to ?-sheet and fibril formation of pEA? (3-42).

SUBMITTER: Dammers C 

PROVIDER: S-EPMC5406372 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature