Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aβ Fibrils by Using MAS Solid-State NMR Spectroscopy

Zheng Niu, Riddhiman Sarkar, Michaela Aichler, Hans Jürgen Wester, Behrooz Hooshyar Yousefi, Bernd Reif

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Positron 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.

Original languageEnglish
Pages (from-to)2495-2502
Number of pages8
JournalChemBioChem
Volume21
Issue number17
DOIs
StatePublished - 1 Sep 2020

Keywords

  • Alzheimer's disease
  • amyloid-beta fibrils
  • deuteration
  • imaging tracer
  • magic angle spinning solid-state NMR spectroscopy
  • positron emission tomography

Fingerprint

Dive into the research topics of 'Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aβ Fibrils by Using MAS Solid-State NMR Spectroscopy'. Together they form a unique fingerprint.

Cite this