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

Authors :: Kunach P
Vaquer-Alicea J
Smith MS
Hopewell R
Monistrol J
Moquin L
Therriault J
Tissot C
Rahmouni N
Massarweh G
Soucy JP
Guiot MC
Shoichet BK
Rosa-Neto P
Diamond MI
Shahmoradian SH
Source :: BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 22. Date of Electronic Publication: 2023 Sep 22.
Publication Year :: 2023
Abstract: 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.<br />Competing Interests: Competing Interests The authors declare no competing interests.