Alzheimer β-Amyloid Homodimers Facilitate Aβ Fibrillization and the Generation of Conformational Antibodies

We reported previously that stabilized β-amyloid peptide dimers were derived from mutant amyloid precursor protein with a single cysteine in the ectodomain juxtamembrane position. In vivo studies revealed that two forms of SDS-stable Aβ homodimers exist, species ending at Aβ40 and Aβ42. The phenomenon of the transformation of the initially deposited 42-residue β-amyloid peptide into the amyloid fibrils of Alzheimer's disease plaques remains to be explained in physical terms, i.e. energetically and structurally. We therefore performed spectroscopic analyses revealing that engineered dimeric peptides ending at residue 42 displayed a much more pronounced β-structural transition than corresponding monomers. Specifically, the single chemically induced dimerization of Aβ peptides significantly increased the β-sheet content by a factor of 2. The C-terminal residues Ile-41 and Ala-42 of dimeric forms further increased the β-sheet content by roughly one-third. In contrast to Aβ42, the β-sheet content of the α- and γ-secretase-generated p3 fragments did not necessarily correlate with the tendency to form fibrils, although p3/17–42 had a pronounced thread forming character with fibril lengths of up to 2.5 μm. Electron microscopic images show that forms of p3/17–42 generated smaller granular particles than forms ending at residue 40. We discuss these findings in terms of Aβ1–42 dimers representing paranuclei, which self-aggregate into ribbon-like ordered fibrils by elongation. Based on Aβ42 dimer-specific titers of a polyclonal antiserum we propose that the Aβ homodimer represents a nidus for plaque formation and a well defined novel therapeutic target.