Anti-β-sheet conformation monoclonal antibody reduces tau and Aβ oligomer pathology in an Alzheimer's disease model

Background: Oligomeric forms of amyloid-beta (A beta) and tau are increasing being recognized as key toxins in the pathogenesis of Alzheimer's disease (AD). Methods: We developed a novel monoclonal antibody (mAb), GW-23B7, that recognizes beta-sheet secondary structure on pathological oligomers of neurodegenerative diseases. Results: The pentameric immunoglobulin M kappa chain (IgM.p) we developed specifically distinguishes intra- and extracellular pathology in human AD brains. Purified GW-23B7 showed a dissociation constant in the nanomolar range for oligomeric A beta and did not bind monomeric A beta. In enzyme-linked immunosorbent assays, it recognized oligomeric forms of both A beta and hyperphosphorylated tau. Aged triple-transgenic AD mice with both A beta and tau pathology infused intraperitoneally for 2 months showed IgM.p in the soluble brain homogenate, peaking at 24 h postinoculation. Treated mice exhibited significant cognitive rescue on radial arm maze testing compared with vehicle control-infused mice. Immunohistochemically, treatment resulted in a significant decrease of extracellular pathology. Biochemically, treatment resulted in significant reductions of oligomeric forms of A beta and tau. Conclusions: These results suggest that GW-23B7, an anti-beta-sheet conformational mAb humanized for clinical trials, may be an effective therapeutic agent for human AD.