Molecular basis for amyloid-β polymorphism

Amyloid-beta (A beta) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A beta molecules form beta-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A beta has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A beta polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A beta. These structures, all of short, self-complementing pairs of beta-sheets termed steric zippers, reveal a variety of modes of self-association of A beta. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A beta. These structures and molecular models contribute fundamental information for understanding A beta polymorphic nature and pathogenesis.