Published in:
ChemBioChem, 21 (2020) 17, Seite 2495-2502
Language:
English
DOI:
10.1002/cbic.202000143
ISSN:
1439-7633;
1439-4227
Origination:
Footnote:
Description:
AbstractPositron emission tomography (PET) tracer molecules like thioflavin T specifically recognize amyloid deposition in brain tissue by selective binding to hydrophobic or aromatic surface grooves on the β‐sheet surface along the fibril axis. The molecular basis of this interaction is, however, not well understood. We have employed magic angle spinning (MAS) solid‐state NMR spectroscopy to characterize Aβ‐PET tracer complexes at atomic resolution. We established a titration protocol by using bovine serum albumin as a carrier to transfer hydrophobic small molecules to Aβ(1‐40) fibrillar aggregates. The same Aβ(1‐40) amyloid fibril sample was employed in subsequent titrations to minimize systematic errors that potentially arise from sample preparation. In the experiments, the small molecules 13C‐methylated Pittsburgh compound B (PiB) as well as a novel Aβ tracer based on a diarylbithiazole (DABTA) scaffold were employed. Classical 13C‐detected as well as proton‐detected spectra of protonated and perdeuterated samples with back‐substituted protons, respectively, were acquired and analyzed. After titration of the tracers, chemical‐shift perturbations were observed in the loop region involving residues Gly25‐Lys28 and Ile32‐Gly33, thus suggesting that the PET tracer molecules interact with the loop region connecting β‐sheets β1 and β2 in Aβ fibrils. We found that titration of the PiB derivatives suppressed fibril polymorphism and stabilized the amyloid fibril structure.