TY - JOUR T1 - Neutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2696 LP - 2702 DO - 10.1523/JNEUROSCI.1676-11.2012 VL - 32 IS - 8 AU - Wagner Zago AU - Manuel Buttini AU - Thomas A. Comery AU - Christopher Nishioka AU - Shyra J. Gardai AU - Peter Seubert AU - Dora Games AU - Frédérique Bard AU - Dale Schenk AU - Gene G. Kinney Y1 - 2012/02/22 UR - http://www.jneurosci.org/content/32/8/2696.abstract N2 - 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 Aβ1–42 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. ER -