Search for neuronal cell death-inhibiting drugs for Alzheimer's disease-relevant signal transduction

本研究旨在探讨阿尔茨海默病（Alzhemer 'sdisease，AD）的神经细胞死亡机制，并鉴定了一种抑制AD相关神经细胞死亡的Humanin（HN）拮抗剂和一种HN受体复合物的内源性激动剂，该复合物由睫状神经营养因子受体（Ciliary Neurotrophic Factor Receptor，WSX-1）/gp 130组成。结果是：（1）莫卡是将APP介导的死亡信号统一为PS介导的死亡信号的关键分子;（2）含有V-set跨膜结构域的2 like通过直接结合抑制HN的活性;（3）一系列实验还表明，在皮肤组织中高表达的钙调素样皮肤蛋白（calmodulin-like skin protein，CLSP）通过血脑屏障转运到中枢神经系统。CLSP通过激活JAK 2/STAT 3轴与HN受体结合抑制家族性AD连锁的V642 I-APP诱导的神经元细胞死亡。这些结果表明，CLSP作为一种生理防御因子在体内抑制AD相关的神经元死亡和功能障碍中发挥主要作用。

In this research program, we have examined the neuronal cell death mechanism underlysing Alzhemer’s disease (AD), and identified an antagonist of Humanin (HN) which inhibited AD-relevant neuronal cell death and an endogenous agonist of HN receoptor complex composed of WSX-1, ciliary neurotrophic factor receptor/gp130. The results were: (1) MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal, (2) V-set transmembrane domain containing 2 like inhibited HN’s activity via direct binding, and (3) A series of experiments also showed that calmodulin-like skin protein (CLSP), highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. CLSP inhibited familial AD-linked V642I-APP-induced neuronal cell death via its binding to HN receptor following activation of JAK2/STAT3 axisThese results suggest that CLSP play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.