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

作者：Hoogerhout Peter^*; Kamphuis Willem; Brugghe Humphrey F; Sluijs Jacqueline A; Timmermans Hans A M; Westdijk Janny; Zomer Gij**ert; Boog Claire J P; Hol Elly M; van den Dobbelsteen Germie P J M

来源：PLos One, 2011, 6(4): e19110.

DOI：10.1371/journal.pone.0019110

The 39- to 42-residue amyloid beta (A beta) 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 A beta immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded A beta, 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 A beta-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide A beta(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 A beta(1-42) oligomers as well as fibrils in this assay. Finally, the antibodies recognized A beta 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.

• 出版日期2011-4-19