ACUTE GAMMA-SECRETASE INHIBITION OF NONHUMAN PRIMATE CNS SHIFTS AMYLOID

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 阿尔茨海默病中淀粉样β蛋白(Abeta)的积聚是由产生和清除的失衡引起的，这导致脑组织中可溶性Abeta物种增加和细胞外斑块形成。目前正在开发多种降低Abeta的治疗方法：一个重要的目标是在接近人类Abeta生理学的模型中表征Abeta以及其他淀粉样前体蛋白(APP)代谢物的分子作用机制和对生理过程的影响。为此，我们报道了将人体体内稳定同位素标记动力学(Silk)方法翻译到恒河猴枕大池(CMP)非人类灵长类动物模型，并使用该模型来测试伽马分泌酶抑制剂(GSI)的作用机制。抑制产生Abeta(β-和伽马-分泌酶)的酶的一个主要问题是，当酶抑制停止时，Abeta的前体可能会积累并导致Abeta产生的快速增加。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues.