β-Amyloid Fibril Structures, In Vitro and In Vivo

Abstract

Since 1998, a great deal of progress has been made towards determining and understanding the molecular structures of amyloid fibrils, including fibrils formed by the β-amyloid peptide that is associated with Alzheimer’s disease. Much of this progress has resulted from solid state nuclear magnetic resonance (NMR) measurements, which provide experimental constraints on molecular conformations and interatomic distances without requiring solubility or crystallinity. In general, amyloid fibrils are polymorphic, meaning that fibrils formed by a given peptide or protein can have multiple, distinct molecular structures, depending on the precise conditions under which the fibrils grow. From solid state NMR, electron microscopy, and other measurements, we have developed two detailed molecular structural models for fibrils formed by the 40-residue wild-type β-amyloid (Aβ1–40) peptide. These two Aβ1–40 fibril polymorphs share a common, parallel β-sheet organization and contain similar peptide conformations but differ in overall symmetry and in other structural aspects. We have also identified and characterized a surprising antiparallel β-sheet structure in metastable fibrils formed by a disease-associated mutant, D23N-Aβ1–40, which reveals how similar sets of interactions can stabilize both parallel and antiparallel β-sheets within amyloid fibrils. We are currently extending our structural studies to β-amyloid fibrils that develop in human brain tissue, with the goal of testing whether variations in fibril structure correlate with variations in severity, progression rate, or other characteristics of Alzheimer’s disease.KeywordsAmyloid FibrilSolid State Nuclear Magnetic ResonanceFibril StructureAmyloid DiseaseMature FibrilThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.