Center for Cognitive Neurology and Department of Neurology, New York University School of Medicine, Alexandria, ERSP Rm 802, 450 East 29th Street, New York, NY, USA.
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
Alzheimers Res Ther. 2018 Jan 29;10(1):10. doi: 10.1186/s13195-018-0337-3.
Oligomeric forms of amyloid-β (Aβ) and tau are increasing being recognized as key toxins in the pathogenesis of Alzheimer's disease (AD).
We developed a novel monoclonal antibody (mAb), GW-23B7, that recognizes β-sheet secondary structure on pathological oligomers of neurodegenerative diseases.
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.
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.
淀粉样β（Aβ）和 tau 的寡聚体形式越来越被认为是阿尔茨海默病（AD）发病机制中的关键毒素。
我们开发了一种新型单克隆抗体（mAb）GW-23B7，它识别神经退行性疾病病理性寡聚体中的β-折叠二级结构。
我们开发的五聚体免疫球蛋白 M kappa 链（IgMκp）特异性区分人类 AD 大脑中的细胞内和细胞外病理学。纯化的 GW-23B7 对寡聚 Aβ表现出纳摩尔范围内的解离常数，并且不结合单体 Aβ。在酶联免疫吸附测定中，它识别 Aβ 和过度磷酸化 tau 的寡聚形式。用含有 Aβ 和 tau 病理学的三转基因 AD 小鼠进行腹腔内输注 2 个月，在接种后 24 小时可溶性脑匀浆中出现 IgMκp。与载体对照输注的小鼠相比，经处理的小鼠在放射臂迷宫测试中表现出显著的认知挽救。免疫组织化学结果表明，治疗导致细胞外病理学显著减少。生物化学结果表明，治疗导致 Aβ 和 tau 的寡聚形式显著减少。
这些结果表明，GW-23B7 是一种针对β-折叠构象的人源化 mAb，可用于临床试验，可能是治疗人类 AD 的有效治疗剂。
