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

γ-分泌酶是一种蛋白酶，催化膜内裂解底物的扩展列表。之一 γ-分泌酶的作用是将Abeta从其前体（APP）上切割下来。由于Abeta的积累被认为是一个 在阿尔茨海默病（AD）发展中的因果作用和γ-分泌酶抑制剂阻断Abeta产生， γ-分泌酶作为AD治疗剂的潜在靶点受到了严格的审查。因此，高度 已经开发出具有优异的体内药理学特性的有效的γ-分泌酶抑制剂， AD的潜在治疗剂。据信这类抑制剂将降低体内的Abeta，防止其在体内的代谢。 积累，并可能对AD有有益作用。然而，也认为γ-分泌酶的效用 抑制剂将受到限制，这是由于抑制了γ-分泌酶调节的信号传导事件， 其他底物，特别是Notch介导的信号传导事件。我们的初步数据表明，这些γ-分泌酶抑制剂可能在AD、癌症、多发性硬化症等多种情况下具有治疗效用， 免疫排斥因此，该计划项目的总体目标是利用口服生物可利用的γ-分泌酶 抑制剂，以严格评估其治疗潜力。更具体地说，我们假设， 在某些条件下抑制APP加工、Notch信号传导和γ-分泌酶的其他生理作用 抑制剂将具有超过潜在毒性有益效果。在这个项目中，我们将1） 开发生物标志物测定，使我们能够评估体内Notch抑制的程度，2）使用γ-分泌酶 抑制剂，以探索体内Abeta降低程度与Abeta改变之间的关系 沉积3）获得关于剂量、APP和Notch的抑制程度以及对所述细胞至关重要的毒性的信息。 4）探讨Notch信号转导的作用及γ-分泌酶介导的抑制对Notch信号转导的影响。 在毒素诱导的脱髓鞘和实验性自身免疫性脑炎的小鼠模型中，

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.