Synthetic Dimeric Aβ(28–40) Mimics the Complex Epitope of Human Anti-Aβ Autoantibodies against Toxic Aβ Oligomers

Abstract

Covalently linked carboxyl-terminal segments of the β-amyloid peptide (Aβ) were tested for their qualification as minimal conformational epitopes of the naturally occurring human autoantibodies against β-amyloid (nAbs-Aβ). nAbs-Aβ specifically recognize the toxic oligomers of Aβ and not the monomeric or the fibrillar forms of Aβ. The synthetic dimers of Aβ(28–40) described herein mimic the toxic Aβ oligomers but are not kinetic intermediates with uncertain compositions. CD spectra identified a surprisingly rich conformational behavior of selected miniamyloids. We observed a highly cooperative conformational transition of β-sheet to α-helix upon the addition of the helix enforcing co-solvent hexafluoroisopropanol. The CD curves of dimer 9 resembled, in a completely reversible manner, the CD spectra measured during the irreversible fibrillation of the parent Aβ(1–40). Synthetic peptide epitopes with high affinities for nAbs-Aβ are needed to identify the physiological roles of nAbs-Aβ and are promising epitopes for vaccination experiments.Background: Human anti-Aβ autoantibodies bind and eliminate toxic oligomers of the Aβ peptide.Results: Synthetic peptides which contain two properly aligned Aβ(28–40) peptides (called miniamyloids) are bound by human anti-Aβ autoantibodies.Conclusion: Synthetic miniamyloids mimic the conformational epitope of the transient toxic Aβ oligomers.Significance: Miniamyloids are expected to become diagnostic tools for the anti-Aβ autoantibodies that are associated with Alzheimer disease. Covalently linked carboxyl-terminal segments of the β-amyloid peptide (Aβ) were tested for their qualification as minimal conformational epitopes of the naturally occurring human autoantibodies against β-amyloid (nAbs-Aβ). nAbs-Aβ specifically recognize the toxic oligomers of Aβ and not the monomeric or the fibrillar forms of Aβ. The synthetic dimers of Aβ(28–40) described herein mimic the toxic Aβ oligomers but are not kinetic intermediates with uncertain compositions. CD spectra identified a surprisingly rich conformational behavior of selected miniamyloids. We observed a highly cooperative conformational transition of β-sheet to α-helix upon the addition of the helix enforcing co-solvent hexafluoroisopropanol. The CD curves of dimer 9 resembled, in a completely reversible manner, the CD spectra measured during the irreversible fibrillation of the parent Aβ(1–40). Synthetic peptide epitopes with high affinities for nAbs-Aβ are needed to identify the physiological roles of nAbs-Aβ and are promising epitopes for vaccination experiments. Background: Human anti-Aβ autoantibodies bind and eliminate toxic oligomers of the Aβ peptide. Results: Synthetic peptides which contain two properly aligned Aβ(28–40) peptides (called miniamyloids) are bound by human anti-Aβ autoantibodies. Conclusion: Synthetic miniamyloids mimic the conformational epitope of the transient toxic Aβ oligomers. Significance: Miniamyloids are expected to become diagnostic tools for the anti-Aβ autoantibodies that are associated with Alzheimer disease.