Molecular basis for amyloid-beta polymorphism.

ABSTRACT: Amyloid-beta (A?) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A? molecules form ?-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? has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A? polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A?. These structures, all of short, self-complementing pairs of ?-sheets termed steric zippers, reveal a variety of modes of self-association of A?. 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?. These structures and molecular models contribute fundamental information for understanding A? polymorphic nature and pathogenesis.

SUBMITTER: Colletier JP 

PROVIDER: S-EPMC3193189 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature