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

Author

Listed:
  • Peter Kunach

    (McGill University
    Peter O’Donnell Jr. Brain Institute)

  • Jaime Vaquer-Alicea

    (Peter O’Donnell Jr. Brain Institute)

  • Matthew S. Smith

    (UCSF
    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
    Montreal Neurological Institute)

  • 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)

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.

Suggested Citation

  • 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, 2024. "Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240," Nature Communications, Nature, vol. 15(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52265-x
    DOI: 10.1038/s41467-024-52265-x
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    References listed on IDEAS

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    1. Paul M. Seidler & Kevin A. Murray & David R. Boyer & Peng Ge & Michael R. Sawaya & Carolyn J. Hu & Xinyi Cheng & Romany Abskharon & Hope Pan & Michael A. DeTure & Christopher K. Williams & Dennis W. D, 2022. "Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Yang Shi & Wenjuan Zhang & Yang Yang & Alexey G. Murzin & Benjamin Falcon & Abhay Kotecha & Mike Beers & Airi Tarutani & Fuyuki Kametani & Holly J. Garringer & Ruben Vidal & Grace I. Hallinan & Tammar, 2021. "Structure-based classification of tauopathies," Nature, Nature, vol. 598(7880), pages 359-363, October.
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