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

Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240...

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Detalles Bibliográficos
Autores principales: Kunach, Peter, Vaquer-Alicea, Jaime, Smith, Matthew S., Hopewell, Robert, Monistrol, Jim, Moquin, Luc, Therriault, Joseph, Tissot, Cecile, Rahmouni, Nesrine, Massarweh, Gassan, Soucy, Jean-Paul, Guiot, Marie-Christine, Shoichet, Brian K., Rosa-Neto, Pedro, Diamond, Marc I., Shahmoradian, Sarah H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542181/
https://www.ncbi.nlm.nih.gov/pubmed/37790438
http://dx.doi.org/10.1101/2023.09.22.558671
Descripción
Sumario:Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined 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 K353, 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.

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