Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid

Diffusible subfibrillar aggregates of amyloid proteins are potent neurotoxins and primary suspects in amyloid diseases including Alzheimer's disease. Despite widespread interest, the molecular structures of the amyloid intermediates and the conformational conversions in amyloid misfolding are poorly understood. Here we present a molecular-level examination of sequence-specific secondary structures and supramolecular structures of a neurotoxic amyloid intermediate of the 40-residue beta-amyloid (A beta) peptide involved in Alzheimer's disease. Using solid-state NMR and electron microscopy, we show that, before fibrillization, natively unstructured monomeric A beta is subject to large conformational changes into a spherical amyloid intermediate of 15-35 nm diameter, which has predominantly parallel beta-sheet structures. Structural comparison with A beta fibrils demonstrates that formation of this beta-sheet intermediate (I-beta) largely defines conformational transitions in amyloid misfolding. Neurotoxicity assays on PC12 cells show that I-beta shows higher toxicity than the fibril, indicating that the beta-sheet formation may trigger neurotoxicity.