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

Alzheimer’s Research & Therapy

Fernando Goñi¹  Mitchell Martá-Ariza¹  Krystal Herline¹  Eleanor Drummond¹  Thomas Wisniewski¹  Allal Boutajangout¹  Frances Prelli¹  Daniel Peyser¹  Pankaj Mehta² 

[1] Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine;Department of Immunology, New York State Institute for Basic Research in Developmental Disabilities;

关键词: Immunomodulation;    Oligomers;    Amyloid-β;    Tau;    Prion;   

DOI  :  10.1186/s13195-018-0337-3

来源: DOAJ

【 摘 要 】

Abstract 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 intra- and 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.

【 授权许可】

Unknown