Stabilization, Assembly, and Toxicity of Trimers Derived from A?.

ABSTRACT: Oligomers of the ?-amyloid peptide A? have emerged as important contributors to neurodegeneration in Alzheimer's disease. Mounting evidence suggests that A? trimers and higher-order oligomers derived from trimers have special significance in the early stages of Alzheimer's disease. Elucidating the structures of these trimers and higher-order oligomers is paramount for understanding their role in neurodegeneration. This paper describes the design, synthesis, X-ray crystallographic structures, and biophysical and biological properties of two stabilized trimers derived from the central and C-terminal regions of A?. These triangular trimers are stabilized through three disulfide cross-links between the monomer subunits. The X-ray crystallographic structures reveal that the stabilized trimers assemble hierarchically to form hexamers, dodecamers, and annular porelike structures. Solution-phase biophysical studies reveal that the stabilized trimers assemble in solution to form oligomers that recapitulate some of the higher-order assemblies observed crystallographically. The stabilized trimers share many of the biological characteristics of oligomers of full-length A?, including toxicity toward a neuronally derived human cell line, activation of caspase-3 mediated apoptosis, and reactivity with the oligomer-specific antibody A11. These studies support the biological significance of the triangular trimer assembly of A? ?-hairpins and may offer a deeper understanding of the molecular basis of Alzheimer's disease.

SUBMITTER: Kreutzer AG 

PROVIDER: S-EPMC5256483 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature