Cryo-EM structures of Tau filaments from Alzheimer’s disease brain

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and there are no mechanism-based therapies. AD is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in cerebral cortex. Neurofibrillary lesions are made of paired helical and straight Tau filaments (PHFs and SFs), whereas Tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of Tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of PHFs and SFs from AD brain. Filament cores are made of two identical protofilaments comprising residues 306–378 of Tau, which adopt a combined cross-β/β-helix structure and define the seed for Tau aggregation. PHFs and SFs differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way to study a range of neurodegenerative diseases.