Department of Biotechnology, College of Life Science and Biotechnology, National Creative Research Initiatives Center For Inflammatory Response Modulation, Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
J Control Release. 2013 Mar 28;166(3):307-15. doi: 10.1016/j.jconrel.2012.12.022. Epub 2013 Jan 5.
Inhibition of the early intracellular event that triggers neurodegenerative cascades and reversal of neuronal cell death are essential for effective treatment of Alzheimer's disease (AD). In this study, a novel therapeutic for AD, a transducible humanin with an extended caspase-3 cleavage sequence (tHN-C3), was developed and showed multiple mechanisms of therapeutic action. These included targeted delivery of anti-apoptotic protein humanin through the blood-brain barrier (BBB) to neuronal cells, specific inhibition of caspase-3 activation to inhibit the early triggering of AD progression, and delivery of humanin into the cytoplasm of neuronal cells undergoing apoptosis where it exerts its anti-apoptotic functions effectively. The tHN-C3 prevented neuronal cell death induced by H2O2, or soluble Aβ42, via Bax binding. In animal models of AD induced by amyloid beta, in Tg2576 mice, and in the rat middle cerebral artery occlusion model of stroke, tHN-C3 effectively prevented neuronal cell death, inflammatory cell infiltration into the brain, and improved cognitive memory. The therapeutic effectiveness of tHN-C3 was comparable to that of Aricept, a clinically approved drug for AD treatment. Therefore, tHN-C3 may be a new remedy with multiple therapeutic functions targeting the early and late stages of neurodegeneration in AD and other brain injuries.
抑制引发神经退行性级联反应的早期细胞内事件和逆转神经元细胞死亡对于有效治疗阿尔茨海默病（AD）至关重要。在这项研究中，开发了一种新型 AD 治疗药物，一种具有延长的 caspase-3 切割序列的可诱导人源素（tHN-C3），并显示出多种治疗作用机制。这些机制包括通过血脑屏障（BBB）将抗凋亡蛋白人源素靶向递送至神经元细胞，特异性抑制 caspase-3 激活以抑制 AD 进展的早期触发，以及将人源素递送至正在凋亡的神经元细胞的细胞质中，从而有效地发挥其抗凋亡功能。tHN-C3 通过与 Bax 结合来阻止由 H2O2 或可溶性 Aβ42 诱导的神经元细胞死亡。在由淀粉样蛋白β诱导的 AD 动物模型中，在 Tg2576 小鼠中，以及在大鼠大脑中动脉闭塞性中风模型中，tHN-C3 有效预防了神经元细胞死亡、炎性细胞浸润到大脑中，并改善了认知记忆。tHN-C3 的治疗效果可与 Aricept 相媲美，Aricept 是一种用于 AD 治疗的临床批准药物。因此，tHN-C3 可能是一种具有多种治疗功能的新疗法，针对 AD 和其他脑损伤的神经退行性变的早期和晚期阶段。
