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Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.
Sci Rep 2015; 5:17338SR

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+Show Affiliations

Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.Macromolecular Crystallography, Max-Planck Institute of Biophysical Chemistry (MPI-BPC), 37077 Göttingen, Germany.SynAging, 54000 Nancy, France.Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.Medical Research Council Technology, 1-3 Burtonhole Lane, London, UK, NW7 1AD.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.Georg-August-University Göttingen, University Medicine Göttingen, Department of Psychiatry and Psychotherapy, Division of Molecular Psychiatry, 37075 Göttingen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26626428

Citation

Antonios, Gregory, et al. "Alzheimer Therapy With an Antibody Against N-terminal Abeta 4-X and Pyroglutamate Abeta 3-X." Scientific Reports, vol. 5, 2015, p. 17338.
Antonios G, Borgers H, Richard BC, et al. Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. Sci Rep. 2015;5:17338.
Antonios, G., Borgers, H., Richard, B. C., Brauβ, A., Meiβner, J., Weggen, S., ... Bayer, T. A. (2015). Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. Scientific Reports, 5, p. 17338. doi:10.1038/srep17338.
Antonios G, et al. Alzheimer Therapy With an Antibody Against N-terminal Abeta 4-X and Pyroglutamate Abeta 3-X. Sci Rep. 2015 Dec 2;5:17338. PubMed PMID: 26626428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. AU - Antonios,Gregory, AU - Borgers,Henning, AU - Richard,Bernhard C, AU - Brauβ,Andreas, AU - Meiβner,Julius, AU - Weggen,Sascha, AU - Pena,Vladimir, AU - Pillot,Thierry, AU - Davies,Sarah L, AU - Bakrania,Preeti, AU - Matthews,David, AU - Brownlees,Janet, AU - Bouter,Yvonne, AU - Bayer,Thomas A, Y1 - 2015/12/02/ PY - 2015/06/16/received PY - 2015/10/28/accepted PY - 2015/12/3/entrez PY - 2015/12/3/pubmed PY - 2016/9/30/medline SP - 17338 EP - 17338 JF - Scientific reports JO - Sci Rep VL - 5 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26626428/Alzheimer_therapy_with_an_antibody_against_N_terminal_Abeta_4_X_and_pyroglutamate_Abeta_3_X_ L2 - http://dx.doi.org/10.1038/srep17338 DB - PRIME DP - Unbound Medicine ER -