학술논문
Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
Document Type
Author
Kunach P; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.; Vaquer-Alicea J; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.; Smith MS; Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA, United States.; Program of Biophysics, UCSF, San Francisco, CA, United States.; Hopewell R; Montreal Neurological Institute, Montreal, Quebec, Canada.; Monistrol J; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.; Moquin L; Montreal Neurological Institute, Montreal, Quebec, Canada.; Therriault J; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Tissot C; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Rahmouni N; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Massarweh G; Montreal Neurological Institute, Montreal, Quebec, Canada.; Soucy JP; Montreal Neurological Institute, Montreal, Quebec, Canada.; Guiot MC; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Montreal Neurological Institute, Montreal, Quebec, Canada.; Shoichet BK; Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA, United States.; Rosa-Neto P; Department of Neurology, McGill University, Montreal, Quebec, Canada.; Diamond MI; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.; Shahmoradian SH; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
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.
Competing Interests: Competing Interests The authors declare no competing interests.
Competing Interests: Competing Interests The authors declare no competing interests.