Speaker

Prof. Anthony Fitzpatrick, Columbia University, Dept. of Biochemistry & Molecular Biophysics (Host: Songi Han and Irene Chen)

Date and Location

Wednesday November 15, 2017 11:00am to 12:00pm

Abstract

Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. Alzheimer’s disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in 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, 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.