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

γ-分泌酶是一种蛋白酶，可催化多种底物的膜内裂解。其中之一 γ-分泌酶的作用是将 Abeta 与其前体 (APP) 裂解。由于 Abeta 积累被认为发挥了 阿尔茨海默氏病 (AD) 发展中的因果作用和 γ-分泌酶抑制剂可阻止 Abeta 的产生， γ-分泌酶作为 AD 治疗的潜在靶点受到密切关注。结果，高度 具有优异体内药理学特性的有效γ-分泌酶抑制剂已被开发为 AD 的潜在治疗剂。据信，此类抑制剂会降低体内 Abeta，防止其发生。 积累，可能对AD有有益作用。然而，人们还认为，γ-分泌酶的效用 由于抑制由γ-分泌酶介导的信号事件，抑制剂将受到限制 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 γ-分泌酶抑制剂可能在 AD、癌症、多发性硬化症和 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利用的γ-分泌酶 抑制剂来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 分泌酶的其他生理效应 抑制剂的有益作用将超过潜在的毒性。嗨，这个项目我们将 1) 开发生物标志物检测，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 减少程度与 Abeta 改变之间的关系 沉积 3) 获取有关 APP 和 Notch 的剂量、抑制程度以及对细胞至关重要的毒性的信息 其他项目和 4) 探索 Notch 单信号的作用以及 γ-分泌酶介导的抑制作用 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，该信号传导。

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.