title: An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice.
abstract: Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 μg, intraperitoneal, weekly) and compare its efficacy with a general Aβ IgG1 monoclonal antibody, 3A1 (200 μg, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed.
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Frost
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Jens-Ulrich
authors.initials: JU
authors.lastname: Rahfeld
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kleinschmidt
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Nuallain
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Le
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Lues
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard NeuroDiscovery Center NeuroBehavior Laboratory Core, Harvard Institutes of Medicine, Boston, MA, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Probiodrug AG, Halle (Saale), Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: clemere@partners.org.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D023582:Alzheimer Vaccines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001921:Brain / Q000378:metabolism; D003071:Cognition; D003072:Cognition Disorders / Q000517:prevention & control*; D007116:Immunization, Passive; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011761:Pyrrolidonecarboxylic Acid / Q000276:immunology*
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D011761:Pyrrolidonecarboxylic Acid
keywords: APPswe/PS1ΔE9; Immunotherapy; Mircrohemorrhage; Pyroglutamate-3 amyloid-beta; Vascular amyloid