Novel monoclonal antibody 3B8 specifically recognizes pyroglutamate-modified amyloid β 3-42 peptide in brain of AD patients and 3xTg-AD transgenic mice.

In addition to the full-length beta-amyloid peptides (Aβ 1-40/42), several Aβ variants, truncated at their N- or C-termini and bearing different post-translational modifications, have been detected in the brain of Alzheimer´s disease (AD) patients. AβN3(pE), an Aβ peptide bearing an amino-terminal pyroglutamate at position 3, is a significant constituent of intracellular, extracellular and vascular Aβ deposits in brain tissue from individuals with AD and Down syndrome. Pioneering immunotherapy studies have primarily focused on the full-length Aβ peptide, disregarding the presence of N-truncated/modified species. However, in recent years, increasing attention has been directed towards AβN3(pE), in both pre-clinical studies and clinical trials. In the present study, we generated and characterized an anti-AβN3(pE) mouse monoclonal antibody (3B8) that recognizes amyloid aggregates in brain tissue from AD patients and in 3xTg-AD transgenic mice. To identify the epitope recognized by 3B8, a library of random heptapeptides fused to the minor coat protein of M13 phage was screened. Results from screening, along with those from ELISA assays against distinct Aβ fragments, suggest recognition of two conformational epitopes present in AβN3(pE) and Aβ 3-42, regardless of the glutamate-pyroglutamate modification. The novel 3B8 antibody may be useful in future therapeutic and diagnostic applications for AD.