Neutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific

Several anti-amyloid beta (A beta) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-A beta antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of A beta 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 A beta 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 A beta species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of A beta(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 A beta moieties. Importantly C-terminal anti-A beta antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-A beta antibodies effectively interact with both soluble and insoluble forms of A beta and therefore appear particularly well suited for testing the A beta hypothesis of AD.