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.

This study reveals near-atomic interfacial details of an Alzheimer’s Positron Emission Tomography (PET) molecule MK-6240 with its target disease marker, tau amyloid, showing MK-6240 mostly interacts with itself, like a pancake stack, which stabilizes an otherwise small interface with the amyloid.

Details

Title
Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240
Author
Kunach, Peter 1 ; Vaquer-Alicea, Jaime 2 ; Smith, Matthew S. 3 ; Monistrol, Jim 4 ; Hopewell, Robert 5 ; Moquin, Luc 5 ; Therriault, Joseph 6   VIAFID ORCID Logo  ; Tissot, Cecile 6   VIAFID ORCID Logo  ; Rahmouni, Nesrine 6 ; Massarweh, Gassan 5 ; Soucy, Jean-Paul 5 ; Guiot, Marie-Christine 7 ; Shoichet, Brian K. 8   VIAFID ORCID Logo  ; Rosa-Neto, Pedro 6   VIAFID ORCID Logo  ; Diamond, Marc I. 2   VIAFID ORCID Logo  ; Shahmoradian, Sarah H. 2   VIAFID ORCID Logo 

1  McGill University, Department of Neurology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); Peter O’Donnell Jr. Brain Institute, Center for Alzheimer’s and Neurodegenerative Diseases, Dallas, US (GRID:grid.14709.3b) 
2  Peter O’Donnell Jr. Brain Institute, Center for Alzheimer’s and Neurodegenerative Diseases, Dallas, US (GRID:grid.14709.3b) 
3  UCSF, Department of Pharmaceutical Chemistry, San Francisco, US (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); UCSF, Program of Biophysics, San Francisco, US (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
4  Peter O’Donnell Jr. Brain Institute, Center for Alzheimer’s and Neurodegenerative Diseases, Dallas, US (GRID:grid.266102.1) 
5  Montreal Neurological Institute, Montreal, Canada (GRID:grid.416102.0) (ISNI:0000 0004 0646 3639) 
6  McGill University, Department of Neurology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
7  McGill University, Department of Neurology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); Montreal Neurological Institute, Montreal, Canada (GRID:grid.416102.0) (ISNI:0000 0004 0646 3639) 
8  UCSF, Department of Pharmaceutical Chemistry, San Francisco, US (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
Pages
8497
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-52265-x
ProQuest document ID
3111717659
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.