Neuronal death-inhibiting therapy for neurodegenerative disease

在这项研究中，我们研究了阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)的神经元死亡机制。我们还进行了基础研究和翻译研究，以寻找内源性神经保护因子人1，早老素(PS)1/PS 2参与转化生长因子β2通过APP诱导的神经元死亡。我们发现pS1/pS2在转化生长因子β-2通过APP诱导的神经元死亡中起重要作用。结论1.MOCA是APP介导的死亡信号与PS介导的死亡信号相统一的关键分子。鉴定EH为人的内源性激动剂。我们发现EH是一种更有效的内源性人素激动剂。脑室或腹膜内注射的EH在体内表现出抗AD相关性痴呆的活性。一系列实验还表明，在皮肤组织中高表达的EH可以通过血脑屏障运输到中枢神经系统。这些结果提示，EH作为一种生理防御因子，在体内抑制AD相关神经元的死亡和功能障碍方面发挥了主要作用。钓鱼时使用的是模仿人类的小化学物质。我们发现，几种小的化学物质诱导了人蛋白受体亚单位的寡聚化。这一结果证实了它们具有人的生物活性。一种有效的人蛋白衍生物Colivelin的临床前试验。我们发现，鼻腔给药的Colivelin可以有效地转运到中枢神经系统，而不需要修饰或切割。ALS的发病机制。我们从未折叠蛋白反应的角度阐明了P56SVAPB诱导ALS的详细机制。我们还发现，TDP-43的低水平过表达通过上调Bim和下调Bclxl来诱导运动神经元死亡。TDP-43诱导的死亡通过其被激活的caspase的切割而减弱。我们最终发现，BTBD-10基因缺陷的线虫表现出触觉神经元死亡和运动异常。

In this study, we have examined the neuronal death mechanism underlying Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). We also performed basic and translational research to search for endogenous neuroprotective factor Humanin.1, The presenilin(PS)1/PS2 involvement of TGFβ2-induced neuronal death via APP. We found that PS1/PS2 are essential for TGFβ2-induced neuronal death via APP. MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal.2. Identification of EH as an endogenous agonist of Humanin. We found that EH is a far more potent endogenous agonist of Humanin. EH, injected intracerebraventricularly or intraperitoneally, showed anti-AD-related dementia activity in vivo. A series of experiments also showed that EH, highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. These results suggest that EH play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.3. Fishing of small chemicals mimicking Humanin. We found that a couple of small chemicals induced the oligomerization of the Humanin receptor subunits. This result confirmed that they have Humanin activity.4. Preclinical test of Colivelin, a potent Humanin derivative. We found that intranasally administered Colivelin was efficiently transported to the central nervous system without modification or cleavage.5. The ALS pathogenesis. We clarified the detailed mechanism underlying P56SVAPB-induced ALS form the standpoint of unfolded protein response. We also found that low-grade overexpression of TDP-43 induces motor neuron death mediated by the upregulation of Bim and the downregulation of Bcl-xL. TDP-43-induced death is attenuated by its cleavage by activated caspases. We finally found that BTBD-10-deficient C. elegans showed death of touch neurons and motor abnormality.