Structures of Oligomers of a Peptide from β‑Amyloid

Amyloid
oligomers play a central role in Alzheimer’s and
other amyloid diseases, and yet the structures of these heterogeneous
and unstable species are not well understood. To better understand
the structures of oligomers formed by amyloid-β peptide (Aβ),
we have incorporated a key amyloidogenic region of Aβ into a
macrocyclic peptide that stabilizes oligomers and facilitates structural
elucidation by X-ray crystallography. This paper reports the crystallographic
structures of oligomers and oligomer assemblies formed by a macrocycle
containing the Aβ15–23 nonapeptide. The macrocycle
forms hydrogen-bonded β-sheets that assemble into cruciform
tetramers consisting of eight β-strands in a two-layered assembly.
Three of the cruciform tetramers assemble into a triangular dodecamer.
These oligomers further assemble in the lattice to form hexagonal
pores. Molecular modeling studies suggest that the natural Aβ
peptide can form similar oligomers and oligomer assemblies. The crystallographic
and molecular modeling studies suggest the potential for interaction
of the oligomers with cell membranes and provide insights into the
role of oligomers in amyloid diseases.