Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.

Gregory Antonios,Thomas A Bayer,Vladimir Pena,Thierry Pillot,Sascha Weggen,Janet Brownlees,Henning Borgers,Yvonne Bouter,Andreas Brauß,Sarah L Davies,Preeti Bakrania,Bernhard C Richard,David Matthews,Julius Meißner

doi:10.1038/srep17338

Gregory Antonios, Thomas A Bayer + Show 12 more

Open Access

https://doi.org/10.1038/srep17338

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Abstract

Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain. Aβ4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aβ4-x and pyroglutamate Aβ3-X mitigated neuron loss in Tg4-42 mice expressing Aβ4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Aβ4-42. NT4X reduced pyroglutamate Aβ3-x, Aβx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aβ1-x and Aβx-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aβ starting with position four in addition to pyroglutamate Aβ3-x is a relevant target to fight Alzheimer’s disease.

Highlights

Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain
We have previously shown that the monoclonal antibody NT4X reacts with N-terminally truncated Aβ pE3-40/42 and Aβ 4-40/42 variants, but not with Aβ 1–40/42 under denaturing and native conditions[20] and confirm this binding profile with direct biophysical binding experiments using Biacore technology (Fig. 1)
We have generated a monoclonal antibody, which binds to both Aβ pE3-42 and Aβ 4-42 truncated N-terminal amyloid low molecular weight oligomers but not to full-length Aβ 1-42 and will protect primary neuronal cultures from toxicity induced by the N-truncated amyloid peptides but not from the full length amyloid peptide

Summary

Introduction

Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aβ4-x and pyroglutamate Aβ3-X mitigated neuron loss in Tg4-42 mice expressing Aβ4-42 and completely rescued spatial reference memory deficits after passive immunization. For the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aβ starting with position four in addition to pyroglutamate Aβ3-x is a relevant target to fight Alzheimer’s disease. Expression of Aβ 4-42 in the brain of transgenic mice (Tg4-42 transgenic line) induced a massive CA1 pyramidal neuron loss in the hippocampus without any plaque formation correlating with age-dependent spatial reference memory deficits[13]. The aim of the project was to explore whether Aβ 4−x is a relevant drug target in AD

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