Novel Mechanisms of NSAID Action in Alzheimer's Disease

描述（由申请人提供）：本提案是一项为期五年的项目更新（第6-10年），旨在加州大学圣地亚哥分校与杰克逊维尔的马约诊所和华盛顿大学圣刘易斯的联合体研究γ-分泌酶调节化合物作为阿尔茨海默病（AD）治疗剂。在最初五年的支持中，我们已经证明非甾体抗炎药（NSAID）具有一种新的次要作用，以不依赖于环氧合酶（考克斯）的方式调节γ-分泌酶的加工。NSAID的一个子集的活性在体外和体内都优先降低淀粉样蛋白生成A 42肽，这使我们提出，这种活性可能是慢性NSAID使用者中AD风险明显降低的一种解释。由于我们已经鉴定了除NSAID之外的许多改变γ分泌酶裂解的化合物，我们现在一般将这些化合物称为γ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，并导致了其他GSM的临床前开发。该PPG的两个主要目标是进一步了解GSMs的作用机制，并测试其在人体中的活性，以及确定其降低AD个体中疾病相关生物标志物的能力。项目1将检查GSM对γ裂解与ε裂解的作用部位，并测试啮齿动物中联合治疗的疗效。项目2，现已纳入前化学核心，将扩展与多种GSM的结合位点相关的研究，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，以更好地定义GSM如何急性改变小鼠AD模型的大脑，CSF和血浆中的A水平。项目1和2将协调检查由这些GSM升高的较短A肽的生物学特性。项目3将确定R-氟比洛芬是否通过经由留置导管测量新合成的A？来降低人CSF中的A？42，并将在一年安慰剂对照双盲治疗研究中通过神经成像测试GSM（布洛芬）是否将减少AD受试者中的疾病相关CSF生物标志物和脑体积变化。这些研究的成功完成将为以下方面提供更深入的了解：1）GSM如何改变γ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NSAID如何在人体中起作用。通过提供有关GAM的额外临床前和临床信息，此类研究应有助于进一步开发GSMs作为阿尔茨海默病治疗剂。

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.