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

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.

• Authors: Gregory Antonios, Henning Borgers, Bernhard C Richard, Andreas Brauß, Julius Meißner, Sascha Weggen, Vladimir Pena, Thierry Pillot, Sarah L Davies, Preeti Bakrania, David Matthews, Janet Brownlees, Yvonne Bouter, Thomas A Bayer
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 17338 (Dec 02 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26626428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Antibodies, Monoclonal, Murine-Derived
• Peptide Fragments
• amyloid beta-protein (1-42)

Topics

• Alzheimer Disease (drug therapy, immunology)
• Amyloid beta-Peptides (immunology)
• Animals
• Antibodies, Monoclonal, Murine-Derived (immunology, pharmacology)
• Disease Models, Animal
• Humans
• Immunization, Passive (methods)
• Mice
• Peptide Fragments (immunology)
• Rats