Abstract

Anthony W.P. Fitzpatrick1, Benjamin Falcon1 , Shaoda He1 , Alexey G. Murzin1 , Garib Murshudov1 , Holly J. Garringer2, R. Anthony Crowther1, Bernardino Ghetti2, Michel Goedert1, Sjors H.W. Scheres1

1 MRC Laboratory of Molecular Biology, Cambridge CB2 0QH , UK 2 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202 , USA

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and there are no mechanism-based therapies. Abundant neurofibrillary lesions and neuritic plaques are the defining pathological characteristics of AD. Paired helical and straight Tau filaments (PHFs and SFs) with the tinctorial and biophysical characteristics of amyloid are the major components of the neurofibrillary lesions. Here, we present the atomic structures of PHFs and SFs extracted from AD brains, as determined by single-particle cryo-electron microscopy (cryo-EM). We show that PHFs and SFs are made of the same protofilament of Tau, but form ultrastructural polymorphs. Details of the atomic structures of PHFs and SFs will be presented, yielding insights into the self-assembly, polymorphisms and propagation of Tau.