Novel Mechanisms of NSAID Action in Alzheimer's Disease

描述(由申请人提供)：本计划项目续展五年(6-10年)，在加州大学圣地亚哥分校与梅奥诊所杰克逊维尔和圣路易斯华盛顿大学联合进行伽马分泌酶调节化合物作为阿尔茨海默病(AD)疗法。在支持的最初五年中，我们已经证明了非类固醇抗炎药(NSAIDs)具有一种新的辅助作用，它以环氧合酶(COX)不依赖的方式调节伽玛分泌酶的处理。在体外和体内，NSAIDs的一个子集的活性优先降低淀粉样蛋白A42肽，这导致我们提出，这种活性可能是慢性NSAID使用者明显降低AD风险的一个解释。除了非甾体类抗炎药外，我们还发现了许多可以改变伽马分泌酶切割的化合物，现在我们将这些化合物统称为伽马分泌酶调节剂(GSM)。我们的研究工作有助于将第一个GSM，R-氟比洛芬(“Flurizan”，更名为Tarenflurbil“)引入临床用于AD治疗的测试，并导致更多GSM的临床前开发。PPG的两个主要目标是进一步了解GSM的作用机制，测试它们在人类中的活性，并确定它们降低AD患者疾病相关生物标志物的能力。项目1将检查GSM的作用部位，以影响伽马和肾上腺素的分裂，并测试联合治疗对啮齿类动物的疗效。项目2现在纳入了以前的化学核心，将扩展与多个GSM结合位置相关的研究，检查GSM在减少A？42产生与抑制A？聚集方面的相对贡献，并进行动物研究，以更好地确定GSM如何显著改变小鼠AD模型脑、脑脊液和血浆中的A？水平。项目1和项目2将协调检查由这些GSM提高的较短A？多肽的生物学特性。项目3将确定R-氟比洛芬是否通过室内导管测量新合成的A？来降低人脑脊液中的A？42，并将在一年的安慰剂对照双盲治疗研究中通过神经成像测试GSM(布洛芬)是否会减少AD患者的疾病相关脑脊液生物标志物和脑体积变化。这些研究的成功完成将提供对1)GSM如何改变伽马裂解，2)GSM如何减弱啮齿动物模型中的AD样表型，以及3)GSM和基于GSM的非类固醇抗炎药如何在人类中发挥作用的更深入的了解。通过提供更多关于GAM的临床前和临床信息，这些研究应该对GSM作为阿尔茨海默氏症疗法的进一步发展做出重大贡献。

DESCRIPTION (provided by applicant): This proposal is for a five year renewal (years 6-10) of a Program Project to pursue gamma-secretase modulating compounds as Alzheimer's disease (AD) therapeutics at the University of California, San Diego, consortium with Mayo Clinic Jacksonville and Washington University, St Louis. In the first five years of support, we have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have a novel secondary action that modulates gamma-secretase processing in a cyclooxygenase (COX) independent manner. The activity of a subset of NSAIDs preferentially lowers the amyloidogenic A¿42 peptide both in vitro and in vivo, leading us to propose that this activity may be one explanation for the apparent risk reduction of AD in chronic NSAID users. As we have identified many compounds in addition to NSAIDs that shift gamma secretase cleavage, we now generically refer to these compounds as gamma-secretase modulators (GSMs). Our research efforts have contributed to the introduction of the first GSM, R-flurbiprofen ("Flurizan" renamed Tarenflurbil") into the clinic for testing in AD treatment, and led to the preclinical development of additional GSMs. The two major goals of this PPG are to further understand the mechanism of action of GSMs, and to test their activity in humans as well as determine their ability to lower disease-associated biomarkers in AD individuals. Project 1 will examine the site of action of GSMs with respect to effects on gamma- versus epsilon-cleavage and test the efficacy of combination treatments in rodents. Project 2, which has now incorporated the former Chemistry Core, will extend studies relating to the binding site of multiple GSMs, examine the relative contribution of GSMs with respect to reducing A¿42 production vs. inhibiting A¿ aggregation, and conduct animal studies to better define how GSMs acutely alter A¿ levels in the brain, CSF, and plasma of mouse AD models. Projects 1 and 2 will coordinately examine the biological properties of shorter A¿ peptides which are elevated by these GSMs. Project 3 will determine if R-flurbiprofen lowers A¿42 in human CSF by measuring newly synthesized A¿ through in-dwelling catheter and will test whether a GSM (ibuprofen) will reduce disease associated CSF biomarkers and brain volumetric changes by neuroimaging in AD subjects in a one year placebo controlled double-blind treatment study. Successful completion of these studies will provide greater insight into 1) how the GSMs shift gamma cleavage, 2) how GSMs attenuate AD-like phenotypes in rodent models, and 3) how GSMs and GSM based NSAIDs may work in humans. By providing additional preclinical and clinical information on GAMs, such studies should contribute significantly to the further development of GSMs as Alzheimer's therapeutics.