Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin.
Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin.
复制标题
DOI：
10.1016/j.jconrel.2012.12.022
复制
发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
T. Park;Seung-Hyung Kim;Yoonchul Shin;Nae-Hyun Lee;R. Lee;Jae-hyuck Shim;L. Glimcher;I. Mook-Jung;Eunji Cheong;Won-Ki Kim;F. Honda;T. Morio;Jong-Soon Lim;Sang-Kyou Lee
中科院分区：
文献类型：
--
作者：
T. Park;Seung-Hyung Kim;Yoonchul Shin;Nae-Hyun Lee;R. Lee;Jae-hyuck Shim;L. Glimcher;I. Mook-Jung;Eunji Cheong;Won-Ki Kim;F. Honda;T. Morio;Jong-Soon Lim;Sang-Kyou Lee
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，开发了一种新的治疗AD的药物，一种具有扩展caspase-3切割序列的可转导人蛋白（tHN-C3），并显示出多种治疗作用机制。其中包括通过血脑屏障（BBB）靶向递送抗凋亡蛋白humanin到神经元细胞，特异性抑制caspase-3激活以抑制早期触发AD进展，以及将humanin递送到发生凋亡的神经元细胞的细胞质中，在那里它有效地发挥其抗凋亡功能。tHN-C3通过Bax结合抑制H2O2或可溶性Aβ42诱导的神经元细胞死亡。在β淀粉样蛋白诱导的AD动物模型、Tg2576小鼠和脑卒中大鼠大脑中动脉闭塞模型中，tHN-C3能有效防止神经元细胞死亡、炎症细胞向脑内浸润、改善认知记忆。tHN-C3的治疗效果与Aricept相当，Aricept是一种临床批准的治疗AD的药物。因此，tHN-C3可能是一种针对阿尔茨海默病和其他脑损伤的早期和晚期神经退行性变具有多种治疗功能的新药物。
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.