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 () and Sarah H. Shahmoradian ()
Additional contact information
Peter Kunach: McGill University
Jaime Vaquer-Alicea: Peter O’Donnell Jr. Brain Institute
Matthew S. Smith: UCSF
Jim Monistrol: Peter O’Donnell Jr. Brain Institute
Robert Hopewell: Montreal Neurological Institute
Luc Moquin: Montreal Neurological Institute
Joseph Therriault: McGill University
Cecile Tissot: McGill University
Nesrine Rahmouni: McGill University
Gassan Massarweh: Montreal Neurological Institute
Jean-Paul Soucy: Montreal Neurological Institute
Marie-Christine Guiot: McGill University
Brian K. Shoichet: UCSF
Pedro Rosa-Neto: McGill University
Marc I. Diamond: Peter O’Donnell Jr. Brain Institute
Sarah H. Shahmoradian: Peter O’Donnell Jr. Brain Institute

Nature Communications, 2024, vol. 15, issue 1, 1-7

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52265-x

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