title: 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.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Gregory
authors.initials: G
authors.lastname: Antonios
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Borgers
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Richard
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brauß
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Julius
authors.initials: J
authors.lastname: Meißner
authors.affiliation: Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.affiliation: Macromolecular Crystallography, Max-Planck Institute of Biophysical Chemistry (MPI-BPC), 37077 Göttingen, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pena
authors.affiliation: SynAging, 54000 Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
authors.affiliation: Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Davies
authors.affiliation: Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.
authors.forename: Preeti
authors.initials: P
authors.lastname: Bakrania
authors.affiliation: Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.affiliation: Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.
authors.forename: Janet
authors.initials: J
authors.lastname: Brownlees
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bouter
authors.affiliation: Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D058846:Antibodies, Monoclonal, Murine-Derived; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)