A Cyclic Undecamer Peptide Mimics a Turn in Folded Alzheimer Amyloid β and Elicits Antibodies against Oligomeric and Fibrillar Amyloid and Plaques

The 39- to 42-residue amyloid β (Aβ) peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD). Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Aβ immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Aβ, which might have a physiologically relevant function. Therefore, we have targeted an immune response on a conformational neo-epitope in misfolded amyloid that is formed in advance of Aβ-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide Aβ(22–28)-YNGK′ elicited specific antibodies in Balb/c mice. These antibodies bound strongly to the homologous cyclic peptide-bovine serum albumin conjugate, but not to the homologous linear peptide-conjugate, as detected in vitro by enzyme-linked immunosorbent assay. The antibodies also bound—although more weakly—to Aβ(1–42) oligomers as well as fibrils in this assay. Finally, the antibodies recognized Aβ deposits in AD mouse and human brain tissue as established by immunohistological staining. We propose that the cyclic peptide conjugate might provide a lead towards a vaccine that could be administered before the onset of AD symptoms. Further investigation of this hypothesis requires immunization of transgenic AD model mice

[Effects of synthetic IgE-mediated peptides and anti-IgE conjugatevaccines in the cardiovascular system of the rat.]

In anaphylactic reactions IgE-mediated effects on the pulmonary and cardiovascular system play a pivotal role. The sequence of amino acids of the chains of the IgE-antibody is known and decapeptides can be synthesized resembling that part of the chains which binds to the mast cells resulting in the release of histamine and leucotrienes. In theory these synthetic decapeptides can be used as the first step for the vaccine development. Another approach would be the construction of peptides with binding capacity but no stimulating activity resulting in the blocking of IgE-binding sites on the target cells. In this feasibility study pilot experiments were performed on the isolated heart of the (actively TNP-ovalbumin sensitized) rat with coronary flow as parameter. Although the pilot experiments indicated an approach leading to either effective peptide antagonists or vaccines it was foreseen that reaching this goal the demand on research capacity would be substantial. In defining priorities the final conclusion was reasched to end these experiments.RIV