Cryo-EM structures of tau filaments from Alzheimer’s disease

Anthony W. P. Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G. Murzin, Garib Murshudov, Holly J. Garringer, R. Anthony Crowther, Bernardino Ghetti, Michel Goedert () and Sjors H. W. Scheres ()
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Anthony W. P. Fitzpatrick: MRC Laboratory of Molecular Biology
Benjamin Falcon: MRC Laboratory of Molecular Biology
Shaoda He: MRC Laboratory of Molecular Biology
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Garib Murshudov: MRC Laboratory of Molecular Biology
Holly J. Garringer: Indiana University School of Medicine
R. Anthony Crowther: MRC Laboratory of Molecular Biology
Bernardino Ghetti: Indiana University School of Medicine
Michel Goedert: MRC Laboratory of Molecular Biology
Sjors H. W. Scheres: MRC Laboratory of Molecular Biology

Nature, 2017, vol. 547, issue 7662, 185-190

Abstract: Abstract Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, 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 paired helical and straight filaments from the brain of an individual with Alzheimer’s disease. Filament cores are made of two identical protofilaments comprising residues 306–378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments 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 for investigation of a range of neurodegenerative diseases.

Date: 2017
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DOI: 10.1038/nature23002

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