Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer’s disease brain tissue

Abstract

AbstractAmyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may underlie variations in clinical and pathological characteristics of Alzheimer’s disease. We report the molecular structure of a specific brain-derived polymorph that has been identified as the most prevalent polymorph of 40-residue Aβ fibrils in cortical tissue of Alzheimer’s disease patients. This structure, developed from cryo-electron microscopy and supported by solid state NMR data, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformation and its organization of cross-β subunits. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.