title: Neutralization of soluble, synaptotoxic amyloid β species by antibodies is epitope specific.
abstract: Several anti-amyloid β (Aβ) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aβ antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aβ plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble Aβ species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of Aβ(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble Aβ moieties. Importantly C-terminal anti-Aβ antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-Aβ antibodies effectively interact with both soluble and insoluble forms of Aβ and therefore appear particularly well suited for testing the Aβ hypothesis of AD.
authors.affiliation: Janssen Alzheimer Immunotherapy Research & Development, South San Francisco, CA 94080, USA. wzago@janimm.com
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.forename: Manuel
authors.initials: M
authors.lastname: Buttini
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Christopher
authors.initials: C
authors.lastname: Nishioka
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Gardai
authors.forename: Peter
authors.initials: P
authors.lastname: Seubert
authors.forename: Dora
authors.initials: D
authors.lastname: Games
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.forename: Gene G
authors.initials: GG
authors.lastname: Kinney
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing; D001526:Behavioral Symptoms / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D001710:Biotin / Q000378:metabolism; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005239:Fear / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000276:immunology / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D012995:Solubility; D050598:Vesicular Glutamate Transport Protein 1 / Q000276:immunology / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism; D000099273:Neurabins
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D057134:Antibodies, Neutralizing; D001710:Biotin; D000939:Epitopes; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D018091:Receptors, AMPA; D050598:Vesicular Glutamate Transport Protein 1; D016875:tau Proteins; D000099273:Neurabins; C489787:MAP2 protein, rat; C075222:amyloid beta-protein (1-42); C053386:drebrins