Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ

Oligomers
of the β-amyloid peptide Aβ have emerged
as important contributors to neurodegeneration in Alzheimer’s
disease. Mounting evidence suggests that Aβ 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 Aβ. 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 Aβ,
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 Aβ β-hairpins and may
offer a deeper understanding of the molecular basis of Alzheimer’s
disease.