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

TitleCryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.
Publication TypeJournal Article
Year of Publication2021
AuthorsShi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang M-K, Scheres SHW, Goedert M
JournalActa Neuropathol
Volume141
Issue5
Pagination697-708
Date Published2021 05
ISSN1432-0533
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.

DOI10.1007/s00401-021-02294-3
Alternate JournalActa Neuropathol
PubMed ID33723967
PubMed Central IDPMC8043864
Grant ListU01 AG057195 / AG / NIA NIH HHS / United States
P30-AG010133 / / Foundation for the National Institutes of Health /
U01-NS110437 / / Foundation for the National Institutes of Health /
MC_UP_A025_1013 / MRC_ / Medical Research Council / United Kingdom
MC_U105184291 / MRC_ / Medical Research Council / United Kingdom