title: Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies.
abstract: Oligomers of the beta-amyloid (Abeta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic Abeta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar Abeta peptide, enabling the generation of highly Abeta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar Abeta in various Abeta preparations. The globulomer-specific antibody A-887755 was able to prevent Abeta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with Abeta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of Abeta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott, D-67061 Ludwigshafen, Germany. heinz.hillen@abbott.com
authors.forename: Heinz
authors.initials: H
authors.lastname: Hillen
authors.forename: Stefan
authors.initials: S
authors.lastname: Barghorn
authors.forename: Andreas
authors.initials: A
authors.lastname: Striebinger
authors.forename: Boris
authors.initials: B
authors.lastname: Labkovsky
authors.forename: Reinhold
authors.initials: R
authors.lastname: Müller
authors.forename: Volker
authors.initials: V
authors.lastname: Nimmrich
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.forename: Claudia
authors.initials: C
authors.lastname: Perez-Cruz
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Auwera
authors.forename: Fred
authors.initials: F
authors.lastname: van Leuven
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gaalen
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Bespalov
authors.forename: Hans
authors.initials: H
authors.lastname: Schoemaker
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ebert
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000276:immunology; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal