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.