Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril

Amyloid-beta (A beta) is present in humans as a 39-to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, A beta(1-40) and A beta(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. A beta(1-42) is the more neurotoxic species, aggre-gatesmuch faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small A beta oligomers are believed to be the neurotoxic species, A beta amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a diseaserelevant A beta(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-beta-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a beta-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.