Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges

Abstract

Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms. One such form, amino-terminally truncated and modified pyroglutamate (pGlu)-3 Aβ peptide appears to play a seminal role for disease initiation, qualifying it as novel target for immunotherapy approaches.

Keywords: Amyloid-β; Glutaminyl cyclases; Immunotherapy; Pyroglutamate-3 Aβ; Vaccine.

Fig. 1

Targeting site for pGlu-3 Aβ-specific therapeutic antibodies. Full-length Aβ is comprised of 40 or 42 amino acids (Aβ 1-40/42). The six N-terminal amino acids of Aβ are depicted by one-letter code of amino acids and chemical structure. pGlu-3 Aβ is a truncated and post-translationally modified variant generated by catalysis of yet unknown proteases and QC/isoQC to convert an N-terminal glutamate residue into a cyclic 5-oxo-proline ring structure (“pGlu”, “pE”). Thereby, a neoepitope is generated that is not present in full-length Aβ molecules. The interaction site of pGlu-3 Aβ-specific antibodies is represented by the line drawn around the pGlu-modified Aβ N-terminus