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

Autor: Goñi, Fernando, Martá-Ariza, Mitchell, Herline, Krystal, Peyser, Daniel, Boutajangout, Allal, Mehta, Pankaj, Drummond, Eleanor, Prelli, Frances, Wisniewski, Thomas
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Zdroj: Alzheimer's Research & Therapy; 1/29/2018, Vol. 10, p1-N.PAG, 16p
Abstrakt: Background: Oligomeric forms of amyloid-β (Aβ) 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 β-sheet secondary structure on pathological oligomers of neurodegenerative diseases. Results: The pentameric immunoglobulin M kappa chain (IgMκp) we developed specifically distinguishes intraand extracellular pathology in human AD brains. Purified GW-23B7 showed a dissociation constant in the nanomolar range for oligomeric Aβ and did not bind monomeric Aβ. In enzyme-linked immunosorbent assays, it recognized oligomeric forms of both Aβ and hyperphosphorylated tau. Aged triple-transgenic AD mice with both Aβ and tau pathology infused intraperitoneally for 2 months showed IgMκp 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 Aβ and tau. Conclusions: These results suggest that GW-23B7, an anti-β-sheet conformational mAb humanized for clinical trials, may be an effective therapeutic agent for human AD. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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