Novel Mechanisms of NSAID Action in Alzheimer's Disease

NSAID 治疗阿尔茨海默病的新机制

• 批准号: 8497559
• 负责人: EDWARD H. KOO
• 金额: $ 137.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497559
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Animals; Attenuated; Binding Sites; Biological; Biological Markers; Brain; California; Chemistry; Chronic; Clinic; Clinical; Development; Disease; Double-Blind Method; Drug effect disorder; Drug user; Goals; Human; Ibuprofen; In Vitro; Individual; Indwelling Catheter; Measures; Mus; Non-Steroidal Anti-Inflammatory Agents; Peptides; Phenotype; Placebo Control; Plasma; Process; Production; Property; Prostaglandin-Endoperoxide Synthase; R-flurbiprofen; Relative (related person); Research; Risk Reduction; Rodent; Rodent Model; Site; Testing; Therapeutic; Universities; Washington; Work; base; efficacy testing; gamma secretase; in vivo; insight; neuroimaging; novel; pre-clinical; programs

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.

描述（由申请人提供）：该提案是一个为期五年（6-10年）的项目项目的续期，旨在研究γ -分泌酶调节化合物作为阿尔茨海默病（AD）的治疗药物，该项目由加州大学圣地亚哥分校与杰克逊维尔梅奥诊所和圣路易斯华盛顿大学联合开展。在前五年的支持中，我们已经证明非甾体抗炎药（NSAIDs）具有一种新的次要作用，以环氧化酶（COX）独立的方式调节γ -分泌酶的加工。非甾体抗炎药亚群的活性在体外和体内都优先降低淀粉样蛋白a¿42肽，这使我们提出这种活性可能是慢性非甾体抗炎药使用者患AD风险明显降低的一个解释。由于除了非甾体抗炎药外，我们已经发现了许多改变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）。我们的研究工作促成了首个GSM， R-flurbiprofen（“Flurizan”更名为Tarenflurbil）进入临床用于阿尔茨海默病治疗的测试，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gsm的作用机制，测试它们在人类中的活性，以及确定它们在AD个体中降低疾病相关生物标志物的能力。项目1将检查GSMs的作用部位对γ -和ε -切割的影响，并在啮齿动物中测试联合治疗的效果。项目2，现在已经纳入了以前的化学核心，将扩展与多种gsm结合位点相关的研究，检查gsm在减少A - 42产生和抑制A - 42聚集方面的相对贡献，并进行动物研究，以更好地确定gsm如何剧烈改变AD小鼠模型中脑、CSF和血浆中的A - 42水平。项目1和2将协调研究这些gsm提高的较短的A¿肽的生物学特性。项目3将通过留置导管测量新合成的A¿来确定r -氟比洛芬是否会降低人脑脊液中的A¿42，并将在为期一年的安慰剂对照双盲治疗研究中测试GSM（布洛芬）是否会通过神经影像学减少AD受试者的疾病相关脑脊液生物标志物和脑容量变化。这些研究的成功完成将为以下方面提供更深入的见解：1)GSM如何改变γ切割，2)GSM如何在啮齿动物模型中减弱ad样表型，以及3)GSM和基于GSM的非甾体抗炎药如何在人类中起作用。通过提供更多关于GAMs的临床前和临床信息，这些研究将对gms作为阿尔茨海默病治疗方法的进一步发展做出重大贡献。

项目成果

Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice.

• DOI: 10.1016/j.bbrc.2016.07.015
• 发表时间: 2016-09
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: S. A. Park;N. Chevallier;Karishma Tejwani;Mary M Hung;H. Maruyama;T. Golde;E. Koo

γ-Secretase inhibitors and modulators.

• DOI: 10.1016/j.bbamem.2013.06.005
• 发表时间: 2013-12
• 期刊: Biochimica et biophysica acta
• 作者: Golde TE;Koo EH;Felsenstein KM;Osborne BA;Miele L
• 通讯作者: Miele L

An NSAID-like compound, FT-9, preferentially inhibits gamma-secretase cleavage of the amyloid precursor protein compared to its effect on amyloid precursor-like protein 1.

• DOI: 10.1021/bi901237k
• 发表时间: 2009-11-24
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Sala Frigerio C;Kukar TL;Fauq A;Engel PC;Golde TE;Walsh DM
• 通讯作者: Walsh DM

γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP).

• DOI: 10.1371/journal.pone.0144758
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lessard CB;Cottrell BA;Maruyama H;Suresh S;Golde TE;Koo EH
• 通讯作者: Koo EH

Differential Inhibition of Signal Peptide Peptidase Family Members by Established γ-Secretase Inhibitors.

• DOI: 10.1371/journal.pone.0128619
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ran Y;Ladd GZ;Ceballos-Diaz C;Jung JI;Greenbaum D;Felsenstein KM;Golde TE
• 通讯作者: Golde TE