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| Home > Workflow collections > Publication Charges > Pyroglutamate-Modified Amyloid- β (3–42) Shows α -Helical Intermediates before Amyloid Formation |
| Home > Workflow collections > Publication Charges > Pyroglutamate-Modified Amyloid- β (3–42) Shows α -Helical Intermediates before Amyloid Formation |
| Journal Article | FZJ-2017-03553 |
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2017
Cell Press
Cambridge, Mass.
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Please use a persistent id in citations: doi:10.1016/j.bpj.2017.03.007
Abstract: Pyroglutamate-modified amyloid-β (pEAβ) has been described as a relevant Aβ species in Alzheimer’s-disease-affected brains, with pEAβ (3–42) as a dominant isoform. Aβ (1–40) and Aβ (1–42) have been well characterized under various solution conditions, including aqueous solutions containing trifluoroethanol (TFE). To characterize structural properties of pEAβ (3–42) possibly underlying its drastically increased aggregation propensity compared to Aβ (1–42), we started our studies in various TFE-water mixtures and found striking differences between the two Aβ species. Soluble pEAβ (3–42) has an increased tendency to form β-sheet-rich structures compared to Aβ (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 pEAβ (3–42) in contrast to Aβ (1–42). NMR spectroscopy was performed for backbone and side-chain chemical-shift assignments of monomeric pEAβ (3–42) in 40% TFE solution. Although the difference between pEAβ (3–42) and Aβ (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 pEAβ (3–42) contains two α-helical regions connected by a flexible linker, whereas the N-terminus remains unstructured. We found that these α-helices act as a transient intermediate to β-sheet and fibril formation of pEAβ (3–42).
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