Immunodominant epitope and properties of pyroglutamate-modified Aβ-specific antibodies produced in rabbits

N-truncated and N-modified forms of amyloid beta (A beta) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as transgenic mouse models of AD. Although the pathological significance of these shortened forms A beta is not completely understood, previous studies have demonstrated that these peptides are significantly more resistant to degradation, aggregate more rapidly in vitro and exhibit similar or, in some cases, increased toxicity in hippocampal neuronal cultures compared to the full length peptides. In the present study we further investigated the mechanisms of toxicity of one of the most abundant N-truncated/modified A beta peptide bearing aminoterminal pyroglutamate at position 3 (A beta N3(pE)). We demonstrated that A beta N3(pE) oligomers induce phosphatidyl serine externalization and membrane damage in SH-SY5Y cells. Also, we produced A beta N3(pE)-specific polyclonal antibodies in rabbit and identified an immunodominant epitope recognized by anti-A beta N3 (pE) antibodies. Our results are important for developing new immunotherapeutic compounds specifically targeting A beta N3(pE) aggregates since the most commonly used immunogens in the majority of vaccines for AD have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length A beta, which is absent in N-amino truncated peptides. (C) 2009 Elsevier B.V. All rights reserved.