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

Abstract 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.