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  • Sobek, JensUniv Zurich, Switzerland (author)

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • 2024
  • SPRINGER,2024
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-206432
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-206432URI
  • https://doi.org/10.1007/s00259-024-06806-7DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|University of Zurich; Olga-Mayenfisch Stiftung; Fondation Gustave et Simone Prevot; Novartis Foundation for Medical-Biological Research; Swiss Center for Applied Human Toxicology [SCAHT-AP_22_02]; Swedish Research Council [2018-05973, SNIC 2022-3-34]
  • PurposeThere is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (alpha Syn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils.MethodsSPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (A beta)42, K18-tau, full-length 2N4R-tau and alpha Syn fibrils. In silico modeling was performed to examine the binding pockets of ligands on alpha Syn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies.ResultsWe optimized the protocol for the immobilization of A beta 42, K18-tau, full-length 2N4R-tau and alpha Syn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for alpha Syn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-alpha Syn positivity in the brains of Parkinson's disease patients and alpha Syn preformed-fibril injected mice, 6E10-positive A beta in arcA beta mice, and AT-8/AT-100-positivity in pR5 mice.ConclusionSPR measurements of small molecules binding to A beta 42, K18/full-length 2N4R-tau and alpha Syn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

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  • Li, JunhaoUppsala Univ, Sweden (author)
  • Combes, Benjamin F.Univ Zurich, Switzerland (author)
  • Gerez, Juan A.Swiss Fed Inst Technol, Switzerland (author)
  • Henrich, Martin T.Philipps Univ Marburg, Germany (author)
  • Geibl, Fanni F.Philipps Univ Marburg, Germany (author)
  • Nilsson, Peter R.Linköpings universitet,Kemi,Tekniska fakulteten(Swepub:liu)petni61 (author)
  • Shi, KuangyuUniv Bern, Switzerland (author)
  • Rominger, AxelUniv Bern, Switzerland (author)
  • Oertel, Wolfgang H.Philipps Univ Marburg, Germany (author)
  • Nitsch, Roger M.Univ Zurich, Switzerland (author)
  • Nordberg, AgnetaKarolinska Inst, Sweden (author)
  • Agren, HansUppsala Univ, Sweden (author)
  • Ni, RuiqingUniv Zurich, Switzerland; Univ Bern, Switzerland (author)
  • Univ Zurich, SwitzerlandUppsala Univ, Sweden (creator_code:org_t)

Related titles

  • In:European Journal of Nuclear Medicine and Molecular Imaging: SPRINGER1619-70701619-7089

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