HAI Book 2025 - Flipbook - Page 374
Kunach, Peter
85
Microscopic visualization of fluorescent MK-6240
Peter Kunach1,2, Matthew S. Smith,, Monika I. Antczak,, Ankit Gupta, Jim Monistrol, Parth
Tripathi, Varun Jalapati, Marie-Christine Guiot, Daniel Stoddard, Sarah H. Shahmoradian,
Brian K. Shoichet, Jaime Vaquer-Alicea, Pedro Rosa-Neto, Joseph M. Ready, Marc I. Diamond
Center for Alzheimer’s and Neurodegenerative Diseases, Peter O’Donnell Jr. Brain Institute, Dallas, TX, US
Department of Neurology, McGill University, Montreal, QC, CA
3
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, US
4
Program of Biophysics, University of California San Francisco, San Francisco, CA, US
5
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, US
6
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, US
1
2
The Positron Emission Tomography (PET) ligand, MK-6240, binds tau filaments from Alzheimer9s disease (AD).
Cryogenic electron microscopy (cryo-EM) has revealed a stacked binding mode for MK-6240 facilitated by
homotypic pi-pi interactions, and a hydrogen bond with the fibril. We leveraged this information to design a
fluorescent analog based on the MK-6240 scaffold. We produced an MK-6240 analog containing a fluorescent
moiety, that binds both recombinant and ex vivo tau filaments. We determined the precise mode of interaction by
cryo-EM. Akin to the parental compound, the analog binds in a columnated fashion via pi-pi interactions, but
forms hydrogen bonds with different tau residues. Fluorescent MK-6240 specifically labels AD tau pathology in
fixed tissue slices. This novel conformation-specific dye may improve development of agents for diagnosis and
therapy of AD.
Keywords: PET, Fluorescence, Cryo-EM, Alzheimer Disease, Tau
HAI2025 - 374
