Molecular Structure of β-Amyloid Fibrils in Alzheimer's Disease Brain Tissue

In vitro, beta-amyloid (A beta) peptides form polymorphic fibrils, with molecular structures that depend on growth conditions, plus various oligomeric and protofibrillar aggregates. Here, we investigate structures of human brain-derived A beta fibrils, using seeded fibril growth from brain extract and data from solid-state nuclear magnetic resonance and electron microscopy. Experiments on tissue from two Alzheimer's disease (AD) patients with distinct clinical histories showed a single predominant 40 residue A beta (A beta 40) fibril structure in each patient; however, the structures were different from one another. A molecular structural model developed for A beta 40 fibrils from one patient reveals features that distinguish in-vivo-from in-vitro-produced fibrils. The data suggest that fibrils in the brain may spread from a single nucleation site, that structural variations may correlate with variations in AD, and that structure-specific amyloid imaging agents may be an important future goal.