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Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

DOI: 10.1007/s00401-021-02294-3 DOI Help

Authors: Yang Shi (MRC Laboratory of Molecular Biology) , Alexey G. Murzin (MRC Laboratory of Molecular Biology) , Benjamin Falcon (MRC Laboratory of Molecular Biology) , Alexander Epstein (MRC Laboratory of Molecular Biology) , Jonathan Machin (MRC Laboratory of Molecular Biology) , Paul Tempest (APRINOIA Therapeutics,) , Kathy L. Newell (Indiana University School of Medicine) , Ruben Vidal (Indiana University School of Medicine) , Holly J. Garringer (Indiana University School of Medicine) , Naruhiko Sahara (National Institutes for Quantum and Radiological Science and Technology) , Makoto Higuchi (National Institutes for Quantum and Radiological Science and Technology) , Bernardino Ghetti (Indiana University School of Medicine) , Ming-Kuei Jang (APRINOIA Therapeutics) , Sjors H. W. Scheres (MRC Laboratory of Molecular Biology) , Michel Goedert (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acta Neuropathologica , VOL 66

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 17434

Open Access Open Access

Abstract: Tau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

Journal Keywords: Positron emission tomography; Alzheimer’s disease; Posterior cortical atrophy; Primary age-related tauopathy; Immunopurification; Electron cryo-microscopy

Diamond Keywords: Alzheimer's Disease

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Documents:
Shi2021_Article_Cryo-EMStructuresOfTauFilament.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Neurodegenerative Diseases Neurology Non-Communicable Diseases

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)