AB AND BEYOND: Y-SECRETASE A DRUG TARGET FOR CNS DISEASE

伽马分泌酶是一种催化一系列不断扩大的底物的膜内裂解的蛋白酶。其中一个 γ-分泌酶的作用是将Abeta从其前体(APP)中分离出来。因为Abeta的积累被认为是在 在阿尔茨海默病(AD)发展中的因果作用和伽马分泌酶抑制剂阻断Abeta的产生， 作为AD治疗的潜在靶点，伽玛分泌酶已经受到了严格的审查。因此，高度 具有良好体内药理学特性的伽马分泌酶的有效抑制剂已被开发为 治疗阿尔茨海默病的潜在药物。据认为，这种抑制剂会降低体内的Abeta，阻止其 积累，并可能对AD有有益的影响。然而，也有人认为，伽马分泌酶的作用 抑制剂将受到限制，因为抑制伽玛分泌酶调节的信号事件由 其他底物，尤其是Notch介导的信号事件。我们的初步数据表明，这些伽马分泌酶抑制剂可能在各种情况下具有治疗作用，如AD、癌症、多发性硬化和 免疫排斥反应。因此，该计划项目的总体主旨是利用口服生物可用的伽马分泌酶。 严格评估其治疗潜力。更具体地说，我们在 某些条件抑制APP处理、Notch信号和伽玛分泌酶的其他生理效应 抑制剂的有益效果将超过潜在的毒性。在这个项目中，我们将1) 开发生物标记物分析，使我们能够评估体内Notch抑制的程度，2)使用伽马分泌酶 探讨体内Abeta降低程度与Abeta改变的关系 沉积3)获取有关APP和Notch的剂量、抑制程度以及对 4)探讨Notch信号通路的作用和γ-分泌酶介导的抑制作用 该信号在毒素诱导的小鼠脱髓鞘和实验性自身免疫性脑炎中起作用。

Gamma-Secretase is a protease that catalyzes intramembrane cleavage of an expanding list of substrates. One of the actions of gamma-secretase is to cleave Abeta from its precursor (APP). As Abeta accumulation is thought to play a causal role in the development of Alzheimer's Disease (AD) and gamma-secretase inhibitors block Abeta production, gamma-secretase has come under intense scrutiny as a potential target for AD therapeutics. As a result, highly potent inhibitors of gamma-secretase with excellent in vivo pharmacologic properties have been developed as potential therapeutic agents for AD. It is believed that such inhibitors will lower Abeta in vivo, prevent its accumulation, and may have beneficial effect on AD. However, it is also believed that the utility of gamma-secretase inhibitors will be limited due to inhibition of gamma-secretase regulated signaling events mediated by other substrates, especially signaling events mediated by Notch. Our preliminary data indicates that these gamma- secretase inhibitors may have therapeutic utility in such diverse settings as AD, cancer, multiple sclerosis, and immune rejection. Thus, the overall thrust of this program project is to utilize an orally bioavailable gamma-secretase inhibitor to rigorously evaluate its therapeutic potential. More specifically, we hypothesize that in certain conditions inhibition of APP processing, Notch signaling, and other physiologic effects of a gamma-secretase inhibitor will have beneficial effects that outweigh potential toxicities. hi this project we will 1) develop biomarker assays that will enable us to evaluate the extent of Notch inhibition in vivo, 2) use gamma-secretase inhibitors to explore the relationship between extent of Abeta reduction in vivo and alteration in Abeta deposition 3) obtain information on dosing, degree of inhibition of APP and Notch, and toxicity vital to the other projects and 4) explore the role of Notch singling and the effect of gamma-secretase mediated inhibition of that signaling in a mouse model of toxin induced demyelination and experimental autoimmune encephalitis.