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	Heinz Hillen, Stefan Barghorn, Andreas Striebinger, Boris Labkovsky, Reinhold Müller, Volker Nimmrich, Marc W Nolte, Claudia Perez-Cruz, Ingrid van der Auwera, Fred van Leuven, Marcel van Gaalen, Anton Y Bespalov, Hans Schoemaker, James P Sullivan, Ulrich Ebert
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 31 Pg. 10369-79 (Aug 04 2010) ISSN: 1529-2401 [Electronic] United States
PMID	20685980 (Publication Type: Journal Article)
Chemical References	Amyloid beta-Peptides Amyloid beta-Protein Precursor Antibodies, Monoclonal
Topics	Alzheimer Disease (drug therapy, immunology) Amyloid beta-Peptides (immunology) Amyloid beta-Protein Precursor (genetics) Analysis of Variance Animals Antibodies, Monoclonal (immunology, therapeutic use) Cells, Cultured Disease Models, Animal Female Hippocampus (cytology, immunology) Immunoprecipitation Male Mice Mice, Transgenic Neurons (cytology, immunology) Rats Rats, Wistar Recognition, Psychology

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