Nature Communications (Oct 2024)

Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

  • Peter Kunach,
  • Jaime Vaquer-Alicea,
  • Matthew S. Smith,
  • Jim Monistrol,
  • Robert Hopewell,
  • Luc Moquin,
  • Joseph Therriault,
  • Cecile Tissot,
  • Nesrine Rahmouni,
  • Gassan Massarweh,
  • Jean-Paul Soucy,
  • Marie-Christine Guiot,
  • Brian K. Shoichet,
  • Pedro Rosa-Neto,
  • Marc I. Diamond,
  • Sarah H. Shahmoradian

DOI
https://doi.org/10.1038/s41467-024-52265-x
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 7

Abstract

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Abstract Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.