C反应蛋白介导大鼠学习记忆障碍及分子生物变化参与阿尔茨海默病发病机制的研究
|
摘要
背景：阿尔茨海默病(Alzheimer's disease, AD)是一种发生于老年期或老年前期的中枢神经系统退行性疾病。AD典型的病理特征为：神经元内纤维缠结(Neufibrillary tangles, NFTs)、细胞外老年斑(Senile plaques, SP)的形成,以及中枢胆碱能神经元的大量死亡与丢失。β淀粉样蛋白(amyloidβ, Aβ)被认为是AD病患者脑组织SP的最主要组成成分,它由β分泌酶和γ分泌酶裂解淀粉样蛋白前体蛋白(amyloid precursor protein, APP)产生。目前,AD发病机制还不是很清楚,但有研究显示β淀粉样蛋白(amyloidβ, Aβ)是各种因素诱发AD的共同通路,是AD形成和发展的关键因素。C反应蛋白(C reactive protein, CRP)是由炎症或组织损伤引起的非特异的急性时相反应中最具代表性的标志物。目前越来越多的研究表明CRP可能参与AD的发病机制,并能恶化认知功能。但仍未有直接的证据证明CRP能导致AD认知障碍,并引起神经化学物质变化。
目的：为探讨CRP对学习记忆及AD发病机制相关分子的影响,通过研究大鼠认知行为的影响及海马和皮层中Aβ产生增多相关的分子(APP、PS-1、PS-2及BACE)和炎症因子(CRP、IL-1β、IL-6及TNF-α)蛋白水平和基因水平的变化,以明确CRP能否介导大鼠学习记忆障碍及其可能机制。继而从细胞水平进一步探索其可能的作用机制。采用PC12细胞为研究对象,系统地研究CRP对PC12细胞毒性作用及可能机制,为CRP成为治疗AD的新靶点提供理论依据。
方法：(1)40只雄性Sprague-Dawley大鼠(220 g～250 g)随机分为正常对照组、假手术组、CRP组和Aβ25-35组。采用双侧脑室立体定位(i.c.v.)注射给药,CRP组和Aβ25-35组分别相应给予CRP(25.6μg/只)和Aβ25-35(10μg/只),假手术组给予等体积空白溶剂；手术14天后,采用Morris水迷宫进行定向航行实验及空间探索实验检测其参照和空间学习记忆能力；在术后第20天采用避暗法检测其长期记忆能力；行为学检测后,采用实时定量逆转录多聚酶链反应(Real-time RT-PCR)和免疫印迹(Western blotting)方法检测海马和皮层组织中与“Aβ假说”分子机制相关分子(APP、PS-1、PS-2及BACE)及“神经炎症假说”分子机制相关炎症因子(CRP、IL-1β、IL-6及TNF-α)的基因和蛋白表达水平变化。(2)CRP的细胞毒性实验：体外培养PC12细胞,应用四甲基偶氮唑蓝法(methyl thiazolyl tetrazolium, MTT)观察不同浓度CRP对细胞活力的影响,并测定细胞外液乳酸脱氢酶(Lactate dehydrogenase, LDH)活力。(3)采用Real-time PCR和酶联免疫吸附法(ELISA)研究在亚毒性浓度下作用48小时,CRP浓度作用(1.25mg/L、2.5mg/L和5 mg/L)对Aβ生成增加相关基因(PS-1, PS-2, BACE-1和APP) mRNA表达和Aβ1-42表达的影响。(4)采用Real-time PCR和酶联免疫吸附法(ELISA)研究在亚毒性浓度下(5mg/L),CRP刺激后不同时间(12小时、24小时和48小时),PC12对Ap生成增加相关基因(PS-1, PS-2, BACE-1和APP) mRNA表达和Aβ1-42表达的影响。
结果：(1)在Morris水迷宫定向航行实验中,游泳轨迹结果表明尽管在训练初期大多数动物都是沿边搜索方式,但正常组和假手术组比CRP组和Aβ组更快地学会直线搜索方式,导致显著缩短潜伏期和游泳路程。实验结果表明,在Day 1各组动物寻找平台的潜伏期和所需游泳路程无显著性差异(F=1.062,P=0.379和F=0.426,P=0.736)；其余四天各组动物寻找平台的潜伏期有显著性差异(分别为F=11.257,P=0.000；F=3.7、49,P=0.021；F=5.569,P=0.003和F=6.359,P=0.002),寻找平台的所需游泳路程有显著性差异(分别为F=7.658,P=0.001；F=5.925,P=0.002；F=5.421,P=0.004和F=5.780,P=0.003)。CRP组大鼠与假手术组大鼠比较,在Day 2、Day 4和Day 5寻找平台的潜伏期有显著性延长(分别为P=0.001；P=0.020和P=0.006),在Day 2、Day 3、Day 4和Day 5寻找平台的所需游泳路程有显著性延长(分别为P=0.001；P=0.039；P=0.027和P=0.035)；Aβ25-35组大鼠与假手术组大鼠比较,在Day 2、Day3、Day 4和Day 5寻找平台的潜伏期有显著性延长(分别为P=0.000；P=0.034；P=0.011和P=0.006),在Day 2、Day 3、Day 4和Day 5寻找平台的所需游泳路程有显著性延长(分别为P=0.001；P=0.002;P=0.011和P=0.026)；但正常组与假手术组相比无显著性差异。空间探索实验中,各组大鼠90秒内游泳的总路程无显著性差异(F=0.157,P=0.925),但各组大鼠90秒内停留在原平台所在象限(即目的象限)的探索时间和探索路程有显著性差异(F=5.405,P=0.004；F=3.221,P=0.036)。与假手术组相比,CRP组和Ap组大鼠90秒内停留在目的象限的探索时间明显缩短(分别为P=0.048和P=0.019)；与假手术组相比, CRP组和Aβ25-35组大鼠90秒内在目的象限探索路程明显缩短(分别为P=0.044和P=0.032)；但正常组与假手术组相比均无显著性差异。提示CRP组和Aβ25-35组大鼠的空间记忆能力损伤。在被动避暗实验的适应训练中,各组大鼠进入暗室的潜伏期无显著性差异(F=0.115,P=0.951),表明各组大鼠间喜暗及钻洞的习性无显著性差异。在测试实验中,各组大鼠进入暗室的潜伏期均有显著性差异(F=6.870,P=0.001)。与假手术组相比,CRP组和Aβ25-35组大鼠均进入暗室的潜伏期明显缩短(分别为P=0.002和P=0.025)；但正常组与假手术组相比均无显著性差异。表明CRP组和Aβ25-35组大鼠的长期记忆受损。大鼠双侧i.c.v.注射后第22天,Real-time PCR结果显示，与假手术组相比,CRP组能显著提高在皮层组织中APP(P=0.031),IL-1β(P=0.000),IL-6(P=0.048),TNF-α(P=0,000),PS-1(P=0.035),PS-2(P=0.025)和内源性CRP(P=0.002)mRNA表达和提高海马组织中APP(P=0.019),IL-1β(P=0.000),IL-6(P=0.014),TNF-α(P=0.007)和内源性CRP(P=0.002)mRNA表达；Ap组也能显著提高在皮层组织中APP(P=0.013),IL-1β(P=0.000),IL-6(P=0.002),TNF-α(P=0.000),PS-1(P=0.033),PS-2(P=0.020)和内源性CRP(P=0.000)mRNA表达和提高海马组织中APP(P=0.004),IL-1β(P=0.000),IL-6(P=0.017),TNF-α(P=0.002)和内源性CRP(P=0.035)mRNA表达。但正常组与假手术组相比均无显著性差异。Western blotting结果表明,与假手术组相比,CRP组能显著提高在皮层组织中APP(P=0.001),IL-1β(P=0.003)和IL-6(P=0.006)蛋白表达和提高海马组织中IL-1β(P=0.000),BACE(P=0.000),TNF-α(P=0.000)和APP(P=0.000)蛋白表达；Aβ组也能显著提高在皮层组织中APP(P=0.002),IL-1β(P=0.020)和IL-6(P=0.024)蛋白表达和提高海马组织中IL-1β(P=0.000),BACE (P=0.000),TNF-α(P=0.000)和APP(P=0.000)蛋白表达。但正常组与假手术组相比无显著性差异。(2)细胞实验结果表明CRP对PC12细胞产生毒性作用,细胞存活率下降,LDH外漏增加,并且呈一定的剂量依赖性；当CRP浓度在12.5 mg/L、25 mg/L、50 mg/L和100 mg/L作用48小时后,与正常对照组比较,细胞存活率显著下降(分别为P=0.000,P=0.001,P=0.003和P=0.003)；细胞LDH外漏显著增加(分别为P=0.001,P=0.007,P=0.032和P=0.042)。(3)在亚毒性浓度下,CRP呈剂量依赖性地提高PS-1, PS-2, BACE-1和APP mRNA表达和Aβ1-42表达。不同浓度CRP (1.25 mg/L、2.5 mg/L和5 mg/L)能提高PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达及显著提高Aβ1-42表达(分别为P=0.001,P=0.000和P=0.000),且呈一定的剂量依赖性；当CRP的浓度为5 mg/L时,PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达显著上升(分别为P=0.000,P=0.000,P=0.000和P=0.000)。(4)CRP呈时间依赖性地提高PS-1, PS-2, BACE-1和APP mRNA表达和Aβ1-42表达。在亚毒性浓度(5 mg/L)下,CRP刺激后不同时间(12小时、24小时和48小时),PC12细胞PS-1, PS-2, BACE-1和APPmRNA表达升高,并显著提高Aβ1-42表达(分别为P=0.026和P=0.001),且呈一定的时间依赖性；当5 mg/L CRP刺激48小时后,PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达显著上升(分别为P=0.000,P=0.003,P=0.000和P=0.003),且BACE-1 mRNA表达在刺激24小时后也显著上升(P=0.009)。
结论：i.c.v.注射CRP后能导致大鼠学习记忆障碍,推测其作用机制：一方面,可能通过上调APP, BACE和PS,进而导致内源性的Aβ大量生成；另一方面,可能通过诱导神经炎症反应发生,从而导致一系列病理损伤,最终导致认知功能障碍；CRP对PC12细胞能产生明显细胞毒性作用,且呈浓度依赖性,其作用机制通过上调APP, PS-1, PS-2和BACE-1的mRNA表达,进而大量生成内源性的Ap,最终产生细胞毒性。CRP可能成为治疗AD的一个新靶点。
Background:Alzheimer's disease (AD) is a progressively neurodegenerative disorder in older. Its pathologycal features include intracellular neurofibrillary tangles(NFT), and senile plaques (SP), which primarily consist of extracellularβ-amyloid peptides (Aβ). Aβpeptides are generated by sequential cleavages of APP byβ-andγ-secretases. Although the pathogenesis of AD is unclear, Ap is considered to be a common factor and key link of AD. C-reactive protein (CRP), a prototypic acute-phase protein, is a sensitive marker of inflammation and tissue damage. There is much evidence showing that CRP may be implicated in the pathogenesis of AD and contribute to the cognitive problem in AD. However, there is no direct evidence showing that CRP impairs memory and causes neurochemical changes as those observed in AD.
Objective:To investigate the effect of CRP, associated with Alzheimer's disease (AD), on cognitive deficits and molecular biologial alteration in rat, we examined the effects of CRP on memory performance and levels of inflammatory cytokines (IL-1βp, IL-6, and TNF-α), CRP, and markers of the endogenous production of Aβ(APP, PS-1, PS-2 and BACE) in rats, which are associated with AD. In addition, in order to further study the mechanism of CRP impair momory, we determined the cytotoxicity of CRP and the concentration and time effects of CRP using PC12 cells.
Methods:(1) Forty Male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into four groups with ten animals each:control (naive animals) group, vehicle group, CRP group, and Aβ25-35 group (positive control). Animals were infused with same voleme of sterile distilled water (vehicle), aggregated Aβ25～35 (10μg/side), or CRP (12.8μg/side) into each cerebral lateral ventricle. Two weeks after operation, the place navigation test and spatial probe test were performed to evaluate both reference and spatial memory in the Morris water-maze. From the 20th to the 21th day, long-term memory was measured by using the passive avoidance test. The mRNA levels of inflammatory cytokines (IL-1β, IL-6, TNF-α), endogenous CRP, APP, PS-1and PS-2 in the hippocampus and cerebral cortex were measured by real time RT-PCR. The protein levels of inflammatory cytokines (IL-1β, IL-6, TNF-α), endogenous APP and BACE in the hippocampus and cerebral cortex were measured by Western blot. (2) In order to investigate the cytotoxicity of CRP, the methyl thiazolyl tetrazolium (MTT) assay was applied to evaluate the cell viability and biochemical method was used to determine the lactate dehydrogenase (LDH) activity in PC 12 cells. (3) In order to investigate the concentration effects of CRP, the mRNA expression levels of PS-1, PS-2, BACE-1 and APP were determined by Real-time PCR and ELISA was applied to evaluate the content of Aβ1-42. (4) In order to investigate the time effects of CRP, the mRNA expression levels of PS-1, PS-2, BACE-1 and APP were determined by Real-time PCR and ELISA was applied to evaluate the content of Aβ1-42.
RESULTS:(1) In the place navigation test, behavioral tracking results revealed that, although most rats showed surrounding searches at the beginning of training, the naive and vehicle-treated rats learned more quickly than the drug-treated rats to swim away from the side walls to find the platform in the target quadrant, leading to shorter escape latency and swimming path length. The latency to reach the platform and the swimming distances during the first training trial were not changed in rats treated with Aβ25-35 or CRP, compared to the vehicle controls. During days 2-5, Aβ25-35-or CRP-treated rats displayed increases in the latency to reach the platform and the swimming distances, relative to vehicle-treated or naive rats (P<0.01, P<0.05.) However, these were no significance between vehicle-treated and naive rats(P>0.05). In the spatial probe trial, the distances traveled in all the four quadrants were not different among groups. Compared to the vehicle control, Aβ25-35 decreased both the duration and swimming distance (P<0.05, P<0.01) in the target quadrant. Similarly, CRP also decreased both indices (P<0.01 for duration and P<0.05 for distance) relative to the vehicle control, suggesting impairment of spatial memory. In addition, all the rats took approximately 23 s before entering the dark compartment, regardless of the treatment during the training; there was no difference among groups (P>0.05). In contrast,24 h after initial training (21d post-infusion), both naive and vehicle-treated rats displayed significantly increases in retention, suggesting that animals remembered the association of the aversive stimulus with the dark compartment. In contrast, the retention was significantly decreased in rats treated with either Aβ25-35 or CRP (P<0.01 and P<0.001, respectively), compared to the vehicle control, suggesting impaired long-term memory. Real-time RT-PCR revealed that both CRP and Aβ25-35 increased the mRNA levels of APP, IL-1β, IL-6, TNF-α, and CRP in the cerebral cortex and hippocampus. Immunoblotting analysis revealed that the protein levels of total APP, IL-1β, and IL-6 were deferentially changed by CRP in the cerebral cortex and hippocampus. The expression of APP, IL-1β, and IL-6 was increased, but that of BACE and TNF-αwas unaltered in the cerebral cortex; in the hippocampus, the expression of all the five proteins except IL-6 was increased. (2) In the cytotoxicity test, the results demonstrated that the concentration-dependent effects of CRP on the viability of PC 12 cells as well as on the LDH leakage of PC 12 cells. The viability significantly decreased and the LDH leakage significantly increased when the PC12 cells treated with CRP at the concentration between 12.5 and 100mg/L for 48h (P<0.01, P<0.05). (3) The concentration-dependent upregulated effects of CRP on the mRNA expression levels of PS-1, PS-2, BACE-1 and APP as well as on the content of Aβ1-42. The content of Aβ1-42 and the mRNA expression levels of PS-1, PS-2, BACE-1 and APP increased significantly while PC12 cells treated with CRP at the subtoxic concentration of 5 mg/L for 48h (P<0.01, P<0.05). (4) The time-dependent upregulated effects of CRP on the mRNA expression levels of PS-1, PS-2, BACE-1 and APP as well as on the content of Aβ1-42. The content of 2 and the mRNA expression levels of PS-1, PS-2, BACE-1 and APP increased significantly while PC 12 cells treated with CRP at the subtoxic concentration of 5 mg/L for 48 h (P<0.01, P<0.05). Particularly, the mRNA expression levels of BACE-1 also significantly increased for 24h (P<0.01)
CONCLUSION:CRP contributes to memory loss and early phase of pathogenesis of AD. CRP can be a novel target for therapeutic intervention in AD, in particular in the memory loss associated with AD.
目的：为探讨CRP对学习记忆及AD发病机制相关分子的影响,通过研究大鼠认知行为的影响及海马和皮层中Aβ产生增多相关的分子(APP、PS-1、PS-2及BACE)和炎症因子(CRP、IL-1β、IL-6及TNF-α)蛋白水平和基因水平的变化,以明确CRP能否介导大鼠学习记忆障碍及其可能机制。继而从细胞水平进一步探索其可能的作用机制。采用PC12细胞为研究对象,系统地研究CRP对PC12细胞毒性作用及可能机制,为CRP成为治疗AD的新靶点提供理论依据。
方法：(1)40只雄性Sprague-Dawley大鼠(220 g～250 g)随机分为正常对照组、假手术组、CRP组和Aβ25-35组。采用双侧脑室立体定位(i.c.v.)注射给药,CRP组和Aβ25-35组分别相应给予CRP(25.6μg/只)和Aβ25-35(10μg/只),假手术组给予等体积空白溶剂；手术14天后,采用Morris水迷宫进行定向航行实验及空间探索实验检测其参照和空间学习记忆能力；在术后第20天采用避暗法检测其长期记忆能力；行为学检测后,采用实时定量逆转录多聚酶链反应(Real-time RT-PCR)和免疫印迹(Western blotting)方法检测海马和皮层组织中与“Aβ假说”分子机制相关分子(APP、PS-1、PS-2及BACE)及“神经炎症假说”分子机制相关炎症因子(CRP、IL-1β、IL-6及TNF-α)的基因和蛋白表达水平变化。(2)CRP的细胞毒性实验：体外培养PC12细胞,应用四甲基偶氮唑蓝法(methyl thiazolyl tetrazolium, MTT)观察不同浓度CRP对细胞活力的影响,并测定细胞外液乳酸脱氢酶(Lactate dehydrogenase, LDH)活力。(3)采用Real-time PCR和酶联免疫吸附法(ELISA)研究在亚毒性浓度下作用48小时,CRP浓度作用(1.25mg/L、2.5mg/L和5 mg/L)对Aβ生成增加相关基因(PS-1, PS-2, BACE-1和APP) mRNA表达和Aβ1-42表达的影响。(4)采用Real-time PCR和酶联免疫吸附法(ELISA)研究在亚毒性浓度下(5mg/L),CRP刺激后不同时间(12小时、24小时和48小时),PC12对Ap生成增加相关基因(PS-1, PS-2, BACE-1和APP) mRNA表达和Aβ1-42表达的影响。
结果：(1)在Morris水迷宫定向航行实验中,游泳轨迹结果表明尽管在训练初期大多数动物都是沿边搜索方式,但正常组和假手术组比CRP组和Aβ组更快地学会直线搜索方式,导致显著缩短潜伏期和游泳路程。实验结果表明,在Day 1各组动物寻找平台的潜伏期和所需游泳路程无显著性差异(F=1.062,P=0.379和F=0.426,P=0.736)；其余四天各组动物寻找平台的潜伏期有显著性差异(分别为F=11.257,P=0.000；F=3.7、49,P=0.021；F=5.569,P=0.003和F=6.359,P=0.002),寻找平台的所需游泳路程有显著性差异(分别为F=7.658,P=0.001；F=5.925,P=0.002；F=5.421,P=0.004和F=5.780,P=0.003)。CRP组大鼠与假手术组大鼠比较,在Day 2、Day 4和Day 5寻找平台的潜伏期有显著性延长(分别为P=0.001；P=0.020和P=0.006),在Day 2、Day 3、Day 4和Day 5寻找平台的所需游泳路程有显著性延长(分别为P=0.001；P=0.039；P=0.027和P=0.035)；Aβ25-35组大鼠与假手术组大鼠比较,在Day 2、Day3、Day 4和Day 5寻找平台的潜伏期有显著性延长(分别为P=0.000；P=0.034；P=0.011和P=0.006),在Day 2、Day 3、Day 4和Day 5寻找平台的所需游泳路程有显著性延长(分别为P=0.001；P=0.002;P=0.011和P=0.026)；但正常组与假手术组相比无显著性差异。空间探索实验中,各组大鼠90秒内游泳的总路程无显著性差异(F=0.157,P=0.925),但各组大鼠90秒内停留在原平台所在象限(即目的象限)的探索时间和探索路程有显著性差异(F=5.405,P=0.004；F=3.221,P=0.036)。与假手术组相比,CRP组和Ap组大鼠90秒内停留在目的象限的探索时间明显缩短(分别为P=0.048和P=0.019)；与假手术组相比, CRP组和Aβ25-35组大鼠90秒内在目的象限探索路程明显缩短(分别为P=0.044和P=0.032)；但正常组与假手术组相比均无显著性差异。提示CRP组和Aβ25-35组大鼠的空间记忆能力损伤。在被动避暗实验的适应训练中,各组大鼠进入暗室的潜伏期无显著性差异(F=0.115,P=0.951),表明各组大鼠间喜暗及钻洞的习性无显著性差异。在测试实验中,各组大鼠进入暗室的潜伏期均有显著性差异(F=6.870,P=0.001)。与假手术组相比,CRP组和Aβ25-35组大鼠均进入暗室的潜伏期明显缩短(分别为P=0.002和P=0.025)；但正常组与假手术组相比均无显著性差异。表明CRP组和Aβ25-35组大鼠的长期记忆受损。大鼠双侧i.c.v.注射后第22天,Real-time PCR结果显示，与假手术组相比,CRP组能显著提高在皮层组织中APP(P=0.031),IL-1β(P=0.000),IL-6(P=0.048),TNF-α(P=0,000),PS-1(P=0.035),PS-2(P=0.025)和内源性CRP(P=0.002)mRNA表达和提高海马组织中APP(P=0.019),IL-1β(P=0.000),IL-6(P=0.014),TNF-α(P=0.007)和内源性CRP(P=0.002)mRNA表达；Ap组也能显著提高在皮层组织中APP(P=0.013),IL-1β(P=0.000),IL-6(P=0.002),TNF-α(P=0.000),PS-1(P=0.033),PS-2(P=0.020)和内源性CRP(P=0.000)mRNA表达和提高海马组织中APP(P=0.004),IL-1β(P=0.000),IL-6(P=0.017),TNF-α(P=0.002)和内源性CRP(P=0.035)mRNA表达。但正常组与假手术组相比均无显著性差异。Western blotting结果表明,与假手术组相比,CRP组能显著提高在皮层组织中APP(P=0.001),IL-1β(P=0.003)和IL-6(P=0.006)蛋白表达和提高海马组织中IL-1β(P=0.000),BACE(P=0.000),TNF-α(P=0.000)和APP(P=0.000)蛋白表达；Aβ组也能显著提高在皮层组织中APP(P=0.002),IL-1β(P=0.020)和IL-6(P=0.024)蛋白表达和提高海马组织中IL-1β(P=0.000),BACE (P=0.000),TNF-α(P=0.000)和APP(P=0.000)蛋白表达。但正常组与假手术组相比无显著性差异。(2)细胞实验结果表明CRP对PC12细胞产生毒性作用,细胞存活率下降,LDH外漏增加,并且呈一定的剂量依赖性；当CRP浓度在12.5 mg/L、25 mg/L、50 mg/L和100 mg/L作用48小时后,与正常对照组比较,细胞存活率显著下降(分别为P=0.000,P=0.001,P=0.003和P=0.003)；细胞LDH外漏显著增加(分别为P=0.001,P=0.007,P=0.032和P=0.042)。(3)在亚毒性浓度下,CRP呈剂量依赖性地提高PS-1, PS-2, BACE-1和APP mRNA表达和Aβ1-42表达。不同浓度CRP (1.25 mg/L、2.5 mg/L和5 mg/L)能提高PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达及显著提高Aβ1-42表达(分别为P=0.001,P=0.000和P=0.000),且呈一定的剂量依赖性；当CRP的浓度为5 mg/L时,PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达显著上升(分别为P=0.000,P=0.000,P=0.000和P=0.000)。(4)CRP呈时间依赖性地提高PS-1, PS-2, BACE-1和APP mRNA表达和Aβ1-42表达。在亚毒性浓度(5 mg/L)下,CRP刺激后不同时间(12小时、24小时和48小时),PC12细胞PS-1, PS-2, BACE-1和APPmRNA表达升高,并显著提高Aβ1-42表达(分别为P=0.026和P=0.001),且呈一定的时间依赖性；当5 mg/L CRP刺激48小时后,PC12细胞对PS-1, PS-2, BACE-1和APP mRNA表达显著上升(分别为P=0.000,P=0.003,P=0.000和P=0.003),且BACE-1 mRNA表达在刺激24小时后也显著上升(P=0.009)。
结论：i.c.v.注射CRP后能导致大鼠学习记忆障碍,推测其作用机制：一方面,可能通过上调APP, BACE和PS,进而导致内源性的Aβ大量生成；另一方面,可能通过诱导神经炎症反应发生,从而导致一系列病理损伤,最终导致认知功能障碍；CRP对PC12细胞能产生明显细胞毒性作用,且呈浓度依赖性,其作用机制通过上调APP, PS-1, PS-2和BACE-1的mRNA表达,进而大量生成内源性的Ap,最终产生细胞毒性。CRP可能成为治疗AD的一个新靶点。
Background:Alzheimer's disease (AD) is a progressively neurodegenerative disorder in older. Its pathologycal features include intracellular neurofibrillary tangles(NFT), and senile plaques (SP), which primarily consist of extracellularβ-amyloid peptides (Aβ). Aβpeptides are generated by sequential cleavages of APP byβ-andγ-secretases. Although the pathogenesis of AD is unclear, Ap is considered to be a common factor and key link of AD. C-reactive protein (CRP), a prototypic acute-phase protein, is a sensitive marker of inflammation and tissue damage. There is much evidence showing that CRP may be implicated in the pathogenesis of AD and contribute to the cognitive problem in AD. However, there is no direct evidence showing that CRP impairs memory and causes neurochemical changes as those observed in AD.
Objective:To investigate the effect of CRP, associated with Alzheimer's disease (AD), on cognitive deficits and molecular biologial alteration in rat, we examined the effects of CRP on memory performance and levels of inflammatory cytokines (IL-1βp, IL-6, and TNF-α), CRP, and markers of the endogenous production of Aβ(APP, PS-1, PS-2 and BACE) in rats, which are associated with AD. In addition, in order to further study the mechanism of CRP impair momory, we determined the cytotoxicity of CRP and the concentration and time effects of CRP using PC12 cells.
Methods:(1) Forty Male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into four groups with ten animals each:control (naive animals) group, vehicle group, CRP group, and Aβ25-35 group (positive control). Animals were infused with same voleme of sterile distilled water (vehicle), aggregated Aβ25～35 (10μg/side), or CRP (12.8μg/side) into each cerebral lateral ventricle. Two weeks after operation, the place navigation test and spatial probe test were performed to evaluate both reference and spatial memory in the Morris water-maze. From the 20th to the 21th day, long-term memory was measured by using the passive avoidance test. The mRNA levels of inflammatory cytokines (IL-1β, IL-6, TNF-α), endogenous CRP, APP, PS-1and PS-2 in the hippocampus and cerebral cortex were measured by real time RT-PCR. The protein levels of inflammatory cytokines (IL-1β, IL-6, TNF-α), endogenous APP and BACE in the hippocampus and cerebral cortex were measured by Western blot. (2) In order to investigate the cytotoxicity of CRP, the methyl thiazolyl tetrazolium (MTT) assay was applied to evaluate the cell viability and biochemical method was used to determine the lactate dehydrogenase (LDH) activity in PC 12 cells. (3) In order to investigate the concentration effects of CRP, the mRNA expression levels of PS-1, PS-2, BACE-1 and APP were determined by Real-time PCR and ELISA was applied to evaluate the content of Aβ1-42. (4) In order to investigate the time effects of CRP, the mRNA expression levels of PS-1, PS-2, BACE-1 and APP were determined by Real-time PCR and ELISA was applied to evaluate the content of Aβ1-42.
RESULTS:(1) In the place navigation test, behavioral tracking results revealed that, although most rats showed surrounding searches at the beginning of training, the naive and vehicle-treated rats learned more quickly than the drug-treated rats to swim away from the side walls to find the platform in the target quadrant, leading to shorter escape latency and swimming path length. The latency to reach the platform and the swimming distances during the first training trial were not changed in rats treated with Aβ25-35 or CRP, compared to the vehicle controls. During days 2-5, Aβ25-35-or CRP-treated rats displayed increases in the latency to reach the platform and the swimming distances, relative to vehicle-treated or naive rats (P<0.01, P<0.05.) However, these were no significance between vehicle-treated and naive rats(P>0.05). In the spatial probe trial, the distances traveled in all the four quadrants were not different among groups. Compared to the vehicle control, Aβ25-35 decreased both the duration and swimming distance (P<0.05, P<0.01) in the target quadrant. Similarly, CRP also decreased both indices (P<0.01 for duration and P<0.05 for distance) relative to the vehicle control, suggesting impairment of spatial memory. In addition, all the rats took approximately 23 s before entering the dark compartment, regardless of the treatment during the training; there was no difference among groups (P>0.05). In contrast,24 h after initial training (21d post-infusion), both naive and vehicle-treated rats displayed significantly increases in retention, suggesting that animals remembered the association of the aversive stimulus with the dark compartment. In contrast, the retention was significantly decreased in rats treated with either Aβ25-35 or CRP (P<0.01 and P<0.001, respectively), compared to the vehicle control, suggesting impaired long-term memory. Real-time RT-PCR revealed that both CRP and Aβ25-35 increased the mRNA levels of APP, IL-1β, IL-6, TNF-α, and CRP in the cerebral cortex and hippocampus. Immunoblotting analysis revealed that the protein levels of total APP, IL-1β, and IL-6 were deferentially changed by CRP in the cerebral cortex and hippocampus. The expression of APP, IL-1β, and IL-6 was increased, but that of BACE and TNF-αwas unaltered in the cerebral cortex; in the hippocampus, the expression of all the five proteins except IL-6 was increased. (2) In the cytotoxicity test, the results demonstrated that the concentration-dependent effects of CRP on the viability of PC 12 cells as well as on the LDH leakage of PC 12 cells. The viability significantly decreased and the LDH leakage significantly increased when the PC12 cells treated with CRP at the concentration between 12.5 and 100mg/L for 48h (P<0.01, P<0.05). (3) The concentration-dependent upregulated effects of CRP on the mRNA expression levels of PS-1, PS-2, BACE-1 and APP as well as on the content of Aβ1-42. The content of Aβ1-42 and the mRNA expression levels of PS-1, PS-2, BACE-1 and APP increased significantly while PC12 cells treated with CRP at the subtoxic concentration of 5 mg/L for 48h (P<0.01, P<0.05). (4) The time-dependent upregulated effects of CRP on the mRNA expression levels of PS-1, PS-2, BACE-1 and APP as well as on the content of Aβ1-42. The content of 2 and the mRNA expression levels of PS-1, PS-2, BACE-1 and APP increased significantly while PC 12 cells treated with CRP at the subtoxic concentration of 5 mg/L for 48 h (P<0.01, P<0.05). Particularly, the mRNA expression levels of BACE-1 also significantly increased for 24h (P<0.01)
CONCLUSION:CRP contributes to memory loss and early phase of pathogenesis of AD. CRP can be a novel target for therapeutic intervention in AD, in particular in the memory loss associated with AD.
引文
[1]2010 Alzheimer's disease facts and figures. Alzheimers Dement.6(2):p. 158-94.
[2]Querfurth, H.W. and F.M. LaFerla, Alzheimer's disease. N Engl J Med.362(4): p.329-44.
[3]Bums, A., Alzheimer's disease:on the verges of treatment and prevention. Lancet Neurol,2009.8(1):p.4-5.
[4]Hogan, D.B., Progress update:Pharmacological treatment of Alzheimer's disease. Neuropsychiatr Dis Treat,2007.3(5):p.569-78.
[5]Mount, C. and C. Downton, Alzheimer disease:progress or profit? Nat Med, 2006.12(7):p.780-4.
[6]Shah, R.S., H.G Lee, Z. Xiongwei, G Perry, M.A. Smith, and R.J. Castellani, Current approaches in the treatment of Alzheimer's disease. Biomed Pharmacother,2008.62(4):p.199-207.
[7]Lemere, C.A. and E. Masliah, Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol.6(2):p.108-19.
[8]Holtzman, J.L., Amyloid-beta vaccination for Alzheimer's dementia. Lancet, 2008.372(9647):p.1381; author reply 1381-2.
[9]McGeer, P.L., Amyloid-beta vaccination for Alzheimer's dementia. Lancet, 2008.372(9647):p.1381; author reply 1381-2.
[10]Vellas, B., Tarenflurbil for Alzheimer's disease:a "shot on goal" that missed. Lancet Neurol.9(3):p.235-7.
[11]Abbott, A., Neuroscience:The plaque plan. Nature,2008.456(7219): p. 161-4.
[12]Miklossy, J., Chronic inflammation and amyloidogenesis in Alzheimer's disease-role of Spirochetes. J Alzheimers Dis,2008.13(4):p.381-91.
[13]Tuppo, E.E. and H.R. Arias, The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol,2005.37(2):p.289-305.
[14]Salminen, A., J. Ojala, A. Kauppinen, K. Kaarniranta, and T. Suuronen, Inflammation in Alzheimer's disease:amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol,2009. 87(3):p.181-94.
[15]Eikelenboom, P., E. van Exel, J.J. Hoozemans, R. Veerhuis, A.J. Rozemuller, and W.A. van Gool, Neuroinflammation-An Early Event in Both the History and Pathogenesis of Alzheimer's Disease. Neurodegener Dis.7(1-3):p.38-41.
[16]Locascio, J.J., H. Fukumoto, L. Yap, T. Bottiglieri, J.H. Growdon, B.T. Hyman, and M.C. Irizarry, Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease. Arch Neurol,2008.65(6):p.776-85.
[17]Volanakis, J.E., Human C-reactive protein:expression, structure, and function. Mol Immunol,2001.38(2-3):p.189-97.
[18]Coventry, B.J., M.L. Ashdown, M.A. Quinn, S.N. Markovic, S.L. Yatomi-Clarke, and A.P. Robinson, CRP identifies homeostatic immune oscillations in cancer patients:a potential treatment targeting tool? J Transl Med,2009.7:p.102.
[19]Kaptoge, S., E. Di Angelantonio, G Lowe, M.B. Pepys, S.G Thompson, R. Collins, and J. Danesh, C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality:an individual participant meta-analysis. Lancet.375(9709):p.132-40.
[20]Black, S., I. Kushner, and D. Samols, C-reactive Protein. J Biol Chem,2004. 279(47):p.48487-90.
[21]Dik, M.G., C. Jonker, C.E. Hack, J.H. Smit, H.C. Comijs, and P. Eikelenboom, Serum inflammatory proteins and cognitive decline in older persons. Neurology,2005.64(8):p.1371-7.
[22]Davis, G.K., N.S. Baboolal, D. Seales, J. Ramchandani, S. McKell, and A. McRae, Potential biomarkers for dementia in Trinidad and Tobago. Neurosci Lett,2007.424(1):p.27-30.
[23]Kuo, H.K., C.J. Yen, C.H. Chang, C.K. Kuo, J.H. Chen, and F. Sorond, Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population:systematic review and meta-analysis. Lancet Neurol, 2005.4(6):p.371-80.
[24]O'Bryant, S.E., S.C. Waring, V. Hobson, J.R. Hall, C.B. Moore, T. Bottiglieri, P. Massman, and R. Diaz-Arrastia, Decreased C-reactive protein levels in Alzheimer disease. J Geriatr Psychiatry Neurol.23(1):p.49-53.
[25]Van Oijen, M., M.P. de Maat, I. Kardys, F.J. de Jong, A. Hofman, P.J. Koudstaal, J.C. Witteman, and M.M. Breteler, Polymorphisms and haplotypes in the C-reactive protein gene and risk of dementia. Neurobiol Aging,2007. 28(9):p.1361-6.
[26]Iwamoto, N., E. Nishiyama, J. Ohwada, and H. Arai, Demonstration of CRP immunoreactivity in brains of Alzheimer's disease:immunohistochemical study using formic acid pretreatment of tissue sections. Neurosci Lett,1994. 177(1-2):p.23-6.
[27]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Human neurons generate C-reactive protein and amyloid P:upregulation in Alzheimer's disease. Brain Res,2000.887(1):p.80-9.
[28]Duong, T., P.J. Acton, and R.A. Johnson, The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions. Brain Res,1998. 813(2):p.303-12.
[29]McGeer, E.G., K. Yasojima, C. Schwab, and P.L. McGeer, The pentraxins: possible role in Alzheimer's disease and other innate inflammatory diseases. Neurobiol Aging,2001.22(6):p.843-8.
[30]Mielke, M.M., P.B. Rosenberg, J. Tschanz, L. Cook, C. Corcoran, K.M. Hayden, M. Norton, P.V. Rabins, R.C. Green, K.A. Welsh-Bohmer, J.C. Breitner, R. Munger, and C.G Lyketsos, Vascular factors predict rate of progression in Alzheimer disease. Neurology,2007.69(19):p.1850-8.
[31]Blaschke, F., D. Bruemmer, F. Yin, Y. Takata, W. Wang, M.C. Fishbein, T. Okura, J. Higaki, K. Graf, E. Fleck, W.A. Hsueh, and R.E. Law, C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation,2004.110(5):p.579-87.
[32]Grad, E., M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E.R. Edelman, and H.D. Danenberg, Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury. Am J Physiol Heart Circ Physiol,2007.293(1):p. H489-95.
[33]Zhang, J., Y.C. Rui, P.Y. Yang, L. Lu, and T.J. Li, C-reactive protein induced expression of adhesion molecules in cultured cerebral microvascular endothelial cells. Life Sci,2006.78(26):p.2983-8.
[34]Gill, R., J.A. Kemp, C. Sabin, and M.B. Pepys, Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats. J Cereb Blood Flow Metab,2004.24(11):p.1214-8.
[35]Nazarov, P.G, I.B. Krylova, N.R. Evdokimova, G.I. Nezhinskaya, and A.A. Butyugov, C-reactive protein:a pentraxin with anti-acetylcholine activity. Life Sci,2007.80(24-25):p.2337-41.
[36]Boekholdt, S.M. and J.J. Kastelein, C-reactive protein and cardiovascular risk: more fuel to the fire. Lancet.375(9709):p.95-6.
[37]Pepys, M.B., G.M. Hirschfield, GA. Tennent, J.R. Gallimore, M.C. Kahan, V. Bellotti, P.N. Hawkins, R.M. Myers, M.D. Smith, A. Polara, A.J. Cobb, S.V. Ley, J.A. Aquilina, C.V. Robinson, I. Sharif, GA. Gray, C.A. Sabin, M.C. Jenvey, S.E. Kolstoe, D. Thompson, and S.P. Wood, Targeting C-reactive protein for the treatment of cardiovascular disease. Nature,2006.440(7088):p. 1217-21.
[38]Kitsis, R.N. and I. Jialal, Limiting myocardial damage during acute myocardial infarction by inhibiting C-reactive protein. N Engl J Med,2006. 355(5):p.513-5.
[39]Raghavendra, V. and S.K. Kulkarni, Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks. Free Radic Biol Med,2001. 30(6):p.595-602.
[40]Affar, E.B., M. Germain, E. Winstall, M. Vodenicharov, R.G Shah, GS. Salvesen, and G.G. Poirier, Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. J Biol Chem,2001. 276(4):p.2935-42.
[41]Fezoui, Y. and D.B. Teplow, Kinetic studies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization. J Biol Chem,2002. 277(40):p.36948-54.
[42]Pallitto, M.M. and R.M. Murphy, A mathematical model of the kinetics of beta-amyloid fibril growth from the denatured state. Biophys J,2001.81(3):p. 1805-22.
[43]Parbhu, A., H. Lin, J. Thimm, and R. Lal, Imaging real-time aggregation of amyloid beta protein (1-42) by atomic force microscopy. Peptides,2002.23(7): p.1265-70.
[44]Serpell, L.C., Alzheimer's amyloid fibrils:structure and assembly. Biochim Biophys Acta,2000.1502(1):p.16-30.
[45]Walsh, D.M., A. Lomakin, G.B. Benedek, M.M. Condron, and D.B. Teplow, Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem,1997.272(35):p.22364-72.
[46]Yankner, B.A., L.K. Duffy, and D.A. Kirschner, Neurotrophic and neurotoxic effects of amyloid beta protein:reversal by tachykinin neuropeptides. Science, 1990.250(4978):p.279-82.
[47]Zheng, W.H., S. Bastianetto, F. Mennicken, W. Ma, and S. Kar, Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience,2002.115(1):p.201-11.
[48]Harkany, T., I. Abraham, C. Konya, C. Nyakas, M. Zarandi, B. Penke, and P.G. Luiten, Mechanisms of beta-amyloid neurotoxicity:perspectives of pharmacotherapy. Rev Neurosci,2000.11(4):p.329-82.
[49]Varadarajan, S., S. Yatin, M. Aksenova, and D.A. Butterfield, Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol,2000.130(2-3):p.184-208.
[50]Pike, C.J., A.J. Walencewicz-Wasserman, J. Kosmoski, D.H. Cribbs, C.G. Glabe, and C.W. Cotman, Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem,1995.64(1):p.253-65.
[51]Laczko, I., S. Holly, Z. Konya, K. Soos, J.L. Varga, M. Hollosi, and B. Penke, Conformational mapping of amyloid peptides from the putative neurotoxic 25-35 region. Biochem Biophys Res Commun,1994.205(1):p.120-6.
[52]Forloni, G, R. Chiesa, S. Smiroldo, L. Verga, M. Salmona, F. Tagliavini, and N. Angeretti, Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35. Neuroreport,1993.4(5):p. 523-6.
[53]Kim, H.S., C.H. Park, S.H. Cha, J.H. Lee, S. Lee, Y. Kim, J.C. Rah, S.J. Jeong, and Y.H. Suh, Carboxyl-terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity. FASEB J,2000.14(11):p.1508-17.
[54]Cheng, G., S.N. Whitehead, V. Hachinski, and D.F. Cechetto, Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis,2006.23(1):p. 140-51.
[55]Tohda, C., N. Matsumoto, K. Zou, M.R. Meselhy, and K. Komatsu, Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, A metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology,2004.29(5):p.860-8.
[56]Stepanichev, M.Y., I.M. Zdobnova, Zarubenko, Ⅱ, Y.V. Moiseeva, N.A. Lazareva, M.V. Onufriev, and N.V. Gulyaeva, Amyloid-beta(25-35)-induced memory impairments correlate with cell loss in rat hippocampus. Physiol Behav,2004.80(5):p.647-55.
[57]Albert, D.J. and G.L. Chew, The septal forebrain and the inhibitory modulation of attack and defense in the rat. A review. Behav Neural Biol, 1980.30(4):p.357-88.
[58]Gray, J.A. and N. McNaughton, Comparison between the behavioural effects of septal and hippocampal lesions:a review. Neurosci Biobehav Rev,1983. 7(2):p.119-88.
[59]Duong, T., M. Nikolaeva, and P.J. Acton, C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease. Brain Res,1997.749(1):p.152-6.
[60]Coughlan, C.M. and K.C. Breen, Factors influencing the processing and function of the amyloid beta precursor protein--a potential therapeutic target in Alzheimer's disease? Pharmacol Ther,2000.86(2):p.111-45.
[61]Stein, T.D., N.J. Anders, C. DeCarli, S.L. Chan, M.P. Mattson, and J.A. Johnson, Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons:support for the amyloid hypothesis. J Neurosci,2004.24(35):p.7707-17.
[62]Racchi, M. and S. Govoni, The pharmacology of amyloid precursor protein processing. Exp Gerontol,2003.38(1-2):p.145-57.
[63]Cappai, R. and A.R. White, Amyloid beta. Int J Biochem Cell Biol,1999. 31(9):p.885-9.
[64]Cole, S.L. and R. Vassar, BACE1 structure and function in health and Alzheimer's disease. Curr Alzheimer Res,2008.5(2):p.100-20.
[65]Golde, T.E. and S.G Younkin, Presenilins as therapeutic targets for the treatment of Alzheimer's disease. Trends Mol Med,2001.7(6):p.264-9.
[66]Octave, J.N., R. Essalmani, B. Tasiaux, J. Menager, C. Czech, and L. Mercken, The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor protein of Alzheimer's disease. J Biol Chem,2000.275(3):p. 1525-8.
[67]Wolfe, M.S., W. Xia, B.L. Ostaszewski, T.S. Diehl, W.T. Kimberly, and D.J. Selkoe, Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature,1999.398(6727):p. 513-7.
[68]Klementiev, B., T. Novikova, V. Novitskaya, P.S. Walmod, O. Dmytriyeva, B. Pakkenberg, V. Berezin, and E. Bock, A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35. Neuroscience,2007.145(1):p.209-24.
[69]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Human neurons generate C-reactive protein and amyloid P:upregulation in Alzheimer's disease. Brain Research,2000.887(1):p.80-89.
[70]McGeer, P.L., E.G McGeer, and K. Yasojima, Alzheimer disease and neuroinflammation. J Neural Transm Suppl,2000.59:p.53-7.
[71]Greene, L.A. and A.S. Tischler, Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A,1976.73(7):p.2424-8.
[72]Schubert, D., S. Heinemann, and Y. Kidokoro, Cholinergic metabolism and synapse formation by a rat nerve cell line. Proc Natl Acad Sci U S A,1977. 74(6):p.2579-83.
[73]Dong, Q. and J.R. Wright, Expression of C-reactive protein by alveolar macrophages. J Immunol,1996.156(12):p.4815-20.
[74]Weinhold, B. and U. Ruther, Interleukin-6-dependent and-independent regulation of the human C-reactive protein gene. Biochem J,1997.327 (Pt 2): p.425-9.
[75]Volanakis, J.E. and A.J. Narkates, Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement. J Immunol,1981. 126(5):p.1820-5.
[76]Volanakis, J.E. and K.W. Wirtz, Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature,1979.281(5727):p.155-7.
[77]Du Clos, T.W., The interaction of C-reactive protein and serum amyloid P component with nuclear antigens. Mol Biol Rep,1996.23(3-4):p.253-60.
[78]Gabay, C. and I. Kushner, Acute-phase proteins and other systemic responses to inflammation. N Engl J Med,1999.340(6):p.448-54.
[79]Szalai, A.J., C-reactive protein (CRP) and autoimmune disease:facts and conjectures. Clin Dev Immunol,2004.11(3-4):p.221-6.
[80]Du Clos, T.W. and C. Mold, C-reactive protein:an activator of innate immunity and a modulator of adaptive immunity. Immunol Res,2004.30(3): p.261-77.
[81]Rogers, J. and L.F. Lue, Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int,2001.39(5-6):p.333-40.
[82]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Up-regulated production and activation of the complement system in Alzheimer's disease brain. Am J Pathol,1999.154(3):p.927-36.
[83]Weggen, S., M. Rogers, and J. Eriksen, NSAIDs:small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol Sci,2007.28(10):p.536-43.
[84]Szekely, C.A., T. Town, and P.P. Zandi, NSAIDs for the chemoprevention of Alzheimer's disease. Subcell Biochem,2007.42:p.229-48.
[85]in t'Veld, B.A., A. Ruitenberg, A. Hofman, L.J. Launer, C.M. van Duijn, T. Stijnen, M.M. Breteler, and B.H. Stricker, Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med,2001.345(21):p. 1515-21.
[86]Schultzberg, M., C. Lindberg, A.F. Aronsson, E. Hjorth, S.D. Spulber, and M. Oprica, Inflammation in the nervous system--physiological and pathophysiological aspects. Physiol Behav,2007.92(1-2):p.121-8.
[87]Griffin, W.S., J.A. Nicoll, L.M. Grimaldi, J.G Sheng, and R.E. Mrak, The pervasiveness of interleukin-1 in alzheimer pathogenesis:a role for specific polymorphisms in disease risk. Exp Gerontol,2000.35(4):p.481-7.
[88]Blasko, I., F. Marx, E. Steiner, T. Hartmann, and B. Grubeck-Loebenstein, TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J,1999.13(1):p.63-8.
[89]Del Bo, R., N. Angeretti, E. Lucca, M.G De Simoni, and G Forloni, Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and [beta]-amyloid production in cultures. Neuroscience Letters,1995.188(1):p. 70-74.
[90]Giovannini, M.G., C. Scali, C. Prosperi, A. Bellucci, M.G. Vannucchi, S. Rosi, G. Pepeu, and F. Casamenti, Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo:involvement of the p38MAPK pathway. Neurobiol Dis,2002.11(2):p.257-74.
[1]Affar, E.B., M. Germain, E. Winstall, M. Vodenicharov, R.G. Shah, G.S. Salvesen, and G.G. Poirier, Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. J Biol Chem,2001. 276(4):p.2935-42.
[2]Barnham, K.J., G.D. Ciccotosto, A.K. Tickler, F.E. Ali, D.G Smith, N.A. Williamson, Y.H. Lam, D. Carrington, D. Tew, G Kocak, I. Volitakis, F. Separovic, C.J. Barrow, J.D. Wade, C.L. Masters, R.A. Cherny, C.C. Curtain, A.I. Bush, and R. Cappai, Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem,2003.278(44):p.42959-65.
[3]Haque, A., N.L. Banik, and S.K. Ray, New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer's disease: cathepsin inhibitors as potential therapeutics. CNS Neurol Disord Drug Targets,2008.7(3):p.270-7.
[4]Goto, M., T. Kimura, S. Hagio, K. Ueda, S. Kitajima, H. Tokunaga, and E. Sato, Neuropathological analysis of dementia in a Japanese leprosarium. Dementia,1995.6(3):p.157-61.
[5]Weggen, S., M. Rogers, and J. Eriksen, NSAIDs:small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol Sci,2007.28(10):p.536-43.
[6]Schultzberg, M., C. Lindberg, A.F. Aronsson, E. Hjorth, S.D. Spulber, and M. Oprica, Inflammation in the nervous system--physiological and pathophysiological aspects. Physiol Behav,2007.92(1-2):p.121-8.
[7]Griffin, W.S., J.A. Nicoll, L.M. Grimaldi, J.G Sheng, and R.E. Mrak, The pervasiveness of interleukin-1 in alzheimer pathogenesis:a role for specific polymorphisms in disease risk. Exp Gerontol,2000.35(4):p.481-7.
[8]Townsend, K.P. and D. Pratico, Novel therapeutic opportunities for Alzheimer's disease:focus on nonsteroidal anti-inflammatory drugs. FASEB J, 2005.19(12):p.1592-601.
[9]McGeer, P.L., M. Schulzer, and E.G McGeer, Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease:a review of 17 epidemiologic studies. Neurology,1996.47(2):p.425-32.
[10]Breitner, J.C., K.A. Welsh, M.J. Helms, P.C. Gaskell, B.A. Gau, A.D. Roses, M.A. Pericak-Vance, and A.M. Saunders, Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging,1995.16(4):p.523-30.
[11]Rogers, J.B., Neuroinflammation in Alzheimer's disease. Neurobiology of Aging,2000.21 (Supplement 1):p.208-208.
[12]Torreilles, F. and J. Touchon, Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease. Prog Neurobiol,2002.66(3):p. 191-203.
[13]Lahiri, D.K., Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene. J Mol Neurosci,2004.23(3):p.225-33.
[14]Pisalyaput, K. and A.J. Tenner, Complement component C1q inhibits beta-amyloid-and serum amyloid P-induced neurotoxicity via caspase-and calpain-independent mechanisms. J Neurochem,2008.104(3):p.696-707.
[15]Lacor, P.N., M.C. Buniel, P.W. Furlow, A.S. Clemente, P.T. Velasco, M. Wood, K.L. Viola, and W.L. Klein, Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci,2007.27(4):p.796-807.
[16]Czirr, E., S. Leuchtenberger, C. Dorner-Ciossek, A. Schneider, M. Jucker, E.H. Koo, C.U. Pietrzik, K. Baumann, and S. Weggen, Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations. J Biol Chem, 2007.282(34):p.24504-13.
[17]Kim, E.J., K.J. Kwon, J.Y. Park, S.H. Lee, C.H. Moon, and E.J. Baik, Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons:associated with iNOS and COX-2. Brain Res,2002.941(1-2):p.1-10.
[18]Jans, D.M., W. Martinet, M. Fillet, M.M. Kockx, M.P. Merville, H. Bult, A.G. Herman, and GR. De Meyer, Effect of non-steroidal anti-inflammatory drugs on amyloid-beta formation and macrophage activation after platelet phagocytosis. J Cardiovasc Pharmacol,2004.43(3):p.462-70.
[19]Cacquevel, M., N. Lebeurrier, S. Cheenne, and D. Vivien, Cytokines in neuroinflammation and Alzheimer's disease. Curr Drug Targets,2004.5(6):p. 529-34.
[20]McGeer, E.G and P.L. McGeer, Neuroinflammation in Alzheimer's Disease and Mild Cognitive Impairment:A Field in Its Infancy. J Alzheimers Dis, 2009.
[21]Ray, B. and D.K. Lahiri, Neuroinflammation in Alzheimer's disease:different molecular targets and potential therapeutic agents including curcumin. Curr Opin Pharmacol,2009.9(4):p.434-44.
[22]Venneti, S., C.A. Wiley, and J. Kofler, Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol,2009. 4(2):p.227-43.
[23]Sastre, M., I. Dewachter, S. Rossner, N. Bogdanovic, E. Rosen, P. Borghgraef, B.O. Evert, L. Dumitrescu-Ozimek, D.R. Thal, G Landreth, J. Walter, T. Klockgether, F. van Leuven, and M.T. Heneka, Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A,2006.103(2):p.443-8.
[24]Weggen, S., J.L. Eriksen, S.A. Sagi, C.U. Pietrzik, V. Ozols, A. Fauq, T.E. Golde, and E.H. Koo, Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem,2003.278(34):p.31831-7.
[25]Valerio, A., F. Boroni, M. Benarese, I. Sarnico, V. Ghisi, L.G Bresciani, M. Ferrario, G Borsani, P. Spano, and M. Pizzi, NF-kappaB pathway:a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci,2006.23(7):p.1711-20.
[26]Casoli, T., G. Di Stefano, B. Giorgetti, M. Balietti, R. Recchioni, F. Moroni, F. Marcheselli, G. Bernardini, P. Fattoretti, and C. Bertoni-Freddari, Platelet as a physiological model to investigate apoptotic mechanisms in Alzheimer beta-amyloid peptide production. Mech Ageing Dev,2008.129(3):p.154-62.
[27]Lee, S.Y, J.W. Lee, H. Lee, H.S. Yoo, Y.P. Yun, K.W. Oh, T.Y. Ha, and J.T. Hong, Inhibitory effect of green tea extract on beta-amyloid-induced PC 12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. Brain Res Mol Brain Res, 2005.140(1-2):p.45-54.
[28]Czirr, E. and S. Weggen, Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds. Neurodegener Dis,2006.3(4-5):p.298-304.
[29]Harkany, T., I. Abraham, C. Konya, C. Nyakas, M. Zarandi, B. Penke, and P.G. Luiten, Mechanisms of beta-amyloid neurotoxicity:perspectives of pharmacotherapy. Rev Neurosci,2000.11(4):p.329-82.
[30]Thomas, T., T.G. Nadackal, and K. Thomas, Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. Neuroreport,2001. 12(15):p.3263-7.
[31]Agdeppa, E.D., V. Kepe, A. Petri, N. Satyamurthy, J. Liu, S.C. Huang, GW. Small, GM. Cole, and J.R. Barrio, In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer's brain using the positron emission tomography molecular imaging probe 2-(1-[6-[(2-[(18)F]fluoroethylXmethyl) amino]-2-naphthyl] ethylidene)malono nitrile. Neuroscience,2003.117(3):p.723-30.
[32]Dokmeci, D., Ibuprofen and Alzheimer's disease. Folia Med (Plovdiv),2004. 46(2):p.5-10.
[33]Schwarzman, A.L., L. Gregori, M.P. Vitek, S. Lyubski, W.J. Strittmatter, J.J. Enghilde, R. Bhasin, J. Silverman, K.H. Weisgraber, P.K. Coyle, and et al., Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci U S A,1994.91(18):p.8368-72.
[34]Ray, I., A. Chauhan, H.M. Wisniewski, J. Wegiel, K.S. Kim, and V.P. Chauhan, Binding of amyloid beta-protein to intracellular brain proteins in rat and human. Neurochem Res,1998.23(10):p.1277-82.
[35]Mazur-Kolecka, B., J. Frackowiak, and H.M. Wisniewski, Apolipoproteins E3 and E4 induce, and transthyretin prevents accumulation of the Alzheimer's beta-amyloid peptide in cultured vascular smooth muscle cells. Brain Res, 1995.698(1-2):p.217-22.
[36]Carro, E., J.L. Trejo, T. Gomez-Isla, D. LeRoith, and I. Torres-Aleman, Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med, 2002.8(12):p.1390-7.
[37]Sousa, J.C., I. Cardoso, F. Marques, M.J. Saraiva, and J.A. Palha, Transthyretin and Alzheimer's disease:where in the brain? Neurobiol Aging, 2007.28(5):p.713-8.
[38]Schultz, K., K. Nilsson, J.E. Nielsen, S.G Lindquist, L.E. Hjermind, B.B. Andersen, A. Wallin, C. Nilsson, and A. Petersen, Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors. Eur J Neurol,2009.
[39]Palha, J.A., P. Moreira, T. Wisniewski, B. Frangione, and M.J. Saraiva, Transthyretin gene in Alzheimer's disease patients. Neurosci Lett,1996. 204(3):p.212-4.
[40]Merched, A., J.M. Serot, S. Visvikis, D. Aguillon, G. Faure, and G. Siest, Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry. FEBS Lett, 1998.425(2):p.225-8.
[41]Skovronsky, D.M., V.M. Lee, and D. Pratico, Amyloid precursor protein and amyloid beta peptide in human platelets. Role of cyclooxygenase and protein kinase C. J Biol Chem,2001.276(20):p.17036-43.
[42]Kinouchi, T., Y. Ono, H. Sorimachi, S. Ishiura, and K. Suzuki, Arachidonate metabolites affect the secretion of an N-terminal fragment of Alzheimer's disease amyloid precursor protein. Biochem Biophys Res Commun,1995. 209(3):p.841-9.
[43]Lee, R.K. and R.J. Wurtman, Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors. Ann N Y Acad Sci, 2000.920:p.261-8.
[44]Gasparini, L., L. Rusconi, H. Xu, P. del Soldato, and E. Ongini, Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J Neurochem,2004.88(2):p.337-48.
[45]Weggen, S., J.L. Eriksen, P. Das, S.A. Sagi, R. Wang, C.U. Pietrzik, K.A. Findlay, T.E. Smith, M.P. Murphy, T. Bulter, D.E. Kang, N. Marquez-Sterling, T.E. Golde, and E.H. Koo, A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature,2001.414(6860):p.212-6.
[46]Avramovich, Y, T. Amit, and M.B. Youdim, Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J Biol Chem,2002.277(35):p.31466-73.
[47]Eriksen, J.L., S.A. Sagi, T.E. Smith, S. Weggen, P. Das, D.C. McLendon, V.V. Ozols, K.W. Jessing, K.H. Zavitz, E.H. Koo, and T.E. Golde, NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest,2003.112(3):p.440-9.
[48]Morihara, T., T. Chu, O. Ubeda, W. Beech, and G.M. Cole, Selective inhibition of Abeta42 production by NSAID R-enantiomers. J Neurochem,2002.83(4): p.1009-12.
[49]Takahashi, Y, I. Hayashi, Y Tominari, K. Rikimaru, Y Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo, Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem,2003.278(20):p.18664-70.
[50]Jantzen, P.T., K.E. Connor, G DiCarlo, G.L. Wenk, J.L. Wallace, A.M. Rojiani, D. Coppola, D. Morgan, and M.N. Gordon, Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci,2002.22(6):p.2246-54.
[51]Kalgutkar, A.S., B.C. Crews, S.W. Rowlinson, A.B. Marnett, K.R. Kozak, R.P. Remmel, and L.J. Marnett, Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors:facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci U S A, 2000.97(2):p.925-30.
[52]Lim, G.P., F. Yang, T. Chu, P. Chen, W. Beech, B. Teter, T. Tran, O. Ubeda, K.H. Ashe, S.A. Frautschy, and GM. Cole, Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci,2000.20(15):p.5709-14.
[53]Yan, Q., J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A.L. Biere, M. Citron, and G Landreth, Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci,2003.23(20):p.7504-9.
[54]Kukar, T., S. Prescott, J.L. Eriksen, V. Holloway, M.P. Murphy, E.H. Koo, T.E. Golde, and M.M. Nicolle, Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci,2007.8:p.54.
[55]Lim, G.R., F. Yang, T. Chu, E. Gahtan, O. Ubeda, W. Beech, J.B. Overmier, K. Hsiao-Ashec, S.A. Frautschy, and GM. Cole, Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging, 2001.22(6):p.983-91.
[56]Bard, F., C. Cannon, R. Barbour, R.L. Burke, D. Games, H. Grajeda, T. Guido, K. Hu, J. Huang, K. Johnson-Wood, K. Khan, D. Kholodenko, M. Lee, I. Lieberburg, R. Motter, M. Nguyen, F. Soriano, N. Vasquez, K. Weiss, B. Welch, P. Seubert, D. Schenk, and T. Yednock, Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med,2000. 6(8):p.916-9.
[57]Sung, S., H. Yang, K. Uryu, E.B. Lee, L. Zhao, D. Shineman, J.Q. Trojanowski, V.M. Lee, and D. Pratico, Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease. Am J Pathol,2004. 165(6):p.2197-206.
[58]Lee, D.W., M.W. Sung, S.W. Park, W.J. Seong, J.L. Roh, B. Park, D.S. Heo, and K.H. Kim, Increased cyclooxygenase-2 expression in human squamous cell carcinomas of the head and neck and inhibition of proliferation by nonsteroidal anti-inflammatory drugs. Anticancer Res,2002.22(4):p. 2089-96.
[59]Xiang, Z., L. Ho, S. Yemul, Z. Zhao, W. Qing, P. Pompl, K. Kelley, A. Dang, D. Teplow, and G.M. Pasinetti, Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr,2002.10(5-6):p.271-8.
[60]Soh, J.W. and I.B. Weinstein, Role of COX-independent targets of NSAIDs and related compounds in cancer prevention and treatment. Prog Exp Tumor Res,2003.37:p.261-85.
[61]Tegeder, I., J. Pfeilschifter, and G. Geisslinger, Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J,2001.15(12):p.2057-72.
[62]Jaradat, M.S., B. Wongsud, S. Phornchirasilp, S.M. Rangwala, G Shams, M. Sutton, K.J. Romstedt, D.J. Noonan, and D.R. Feller, Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. Biochem Pharmacol,2001.62(12):p.1587-95.
[63]Wick, M., G Hurteau, C. Dessev, D. Chan, M.W. Geraci, R.A. Winn, L.E. Heasley, and R.A. Nemenoff, Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. Mol Pharmacol,2002.62(5):p.1207-14.
[64]Pang, L., M. Nie, L. Corbett, and A.J. Knox, Cyclooxygenase-2 expression by nonsteroidal anti-inflammatory drugs in human airway smooth muscle cells: role of peroxisome proliferator-activated receptors. J Immunol,2003.170(2): p.1043-51.
[65]Blasko, I., A. Apochal, G. Boeck, T. Hartmann, B. Grubeck-Loebenstein, and G Ransmayr, Ibuprofen decreases cytokine-induced amyloid beta production in neuronal cells. Neurobiol Dis,2001.8(6):p.1094-101.
[66]Zhou, Y., Y. Su, B. Li, F. Liu, J.W. Ryder, X. Wu, P.A. Gonzalez-DeWhitt, V. Gelfanova, J.E. Hale, P.C. May, S.M. Paul, and B. Ni, Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science,2003.302(5648):p.1215-7.
[67]Herrmann, C., C. Block, C. Geisen, K. Haas, C. Weber, G Winde, T. Moroy, and O. Muller, Sulindac sulfide inhibits Ras signaling. Oncogene,1998. 17(14):p.1769-76.
[68]Gala, M., R. Sun, and V.W. Yang, Inhibition of cell transformation by sulindac sulfide is confined to-specific oncogenic pathways. Cancer Lett,2002.175(1): p.89-94.
[2]Querfurth, H.W. and F.M. LaFerla, Alzheimer's disease. N Engl J Med.362(4): p.329-44.
[3]Bums, A., Alzheimer's disease:on the verges of treatment and prevention. Lancet Neurol,2009.8(1):p.4-5.
[4]Hogan, D.B., Progress update:Pharmacological treatment of Alzheimer's disease. Neuropsychiatr Dis Treat,2007.3(5):p.569-78.
[5]Mount, C. and C. Downton, Alzheimer disease:progress or profit? Nat Med, 2006.12(7):p.780-4.
[6]Shah, R.S., H.G Lee, Z. Xiongwei, G Perry, M.A. Smith, and R.J. Castellani, Current approaches in the treatment of Alzheimer's disease. Biomed Pharmacother,2008.62(4):p.199-207.
[7]Lemere, C.A. and E. Masliah, Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol.6(2):p.108-19.
[8]Holtzman, J.L., Amyloid-beta vaccination for Alzheimer's dementia. Lancet, 2008.372(9647):p.1381; author reply 1381-2.
[9]McGeer, P.L., Amyloid-beta vaccination for Alzheimer's dementia. Lancet, 2008.372(9647):p.1381; author reply 1381-2.
[10]Vellas, B., Tarenflurbil for Alzheimer's disease:a "shot on goal" that missed. Lancet Neurol.9(3):p.235-7.
[11]Abbott, A., Neuroscience:The plaque plan. Nature,2008.456(7219): p. 161-4.
[12]Miklossy, J., Chronic inflammation and amyloidogenesis in Alzheimer's disease-role of Spirochetes. J Alzheimers Dis,2008.13(4):p.381-91.
[13]Tuppo, E.E. and H.R. Arias, The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol,2005.37(2):p.289-305.
[14]Salminen, A., J. Ojala, A. Kauppinen, K. Kaarniranta, and T. Suuronen, Inflammation in Alzheimer's disease:amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol,2009. 87(3):p.181-94.
[15]Eikelenboom, P., E. van Exel, J.J. Hoozemans, R. Veerhuis, A.J. Rozemuller, and W.A. van Gool, Neuroinflammation-An Early Event in Both the History and Pathogenesis of Alzheimer's Disease. Neurodegener Dis.7(1-3):p.38-41.
[16]Locascio, J.J., H. Fukumoto, L. Yap, T. Bottiglieri, J.H. Growdon, B.T. Hyman, and M.C. Irizarry, Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease. Arch Neurol,2008.65(6):p.776-85.
[17]Volanakis, J.E., Human C-reactive protein:expression, structure, and function. Mol Immunol,2001.38(2-3):p.189-97.
[18]Coventry, B.J., M.L. Ashdown, M.A. Quinn, S.N. Markovic, S.L. Yatomi-Clarke, and A.P. Robinson, CRP identifies homeostatic immune oscillations in cancer patients:a potential treatment targeting tool? J Transl Med,2009.7:p.102.
[19]Kaptoge, S., E. Di Angelantonio, G Lowe, M.B. Pepys, S.G Thompson, R. Collins, and J. Danesh, C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality:an individual participant meta-analysis. Lancet.375(9709):p.132-40.
[20]Black, S., I. Kushner, and D. Samols, C-reactive Protein. J Biol Chem,2004. 279(47):p.48487-90.
[21]Dik, M.G., C. Jonker, C.E. Hack, J.H. Smit, H.C. Comijs, and P. Eikelenboom, Serum inflammatory proteins and cognitive decline in older persons. Neurology,2005.64(8):p.1371-7.
[22]Davis, G.K., N.S. Baboolal, D. Seales, J. Ramchandani, S. McKell, and A. McRae, Potential biomarkers for dementia in Trinidad and Tobago. Neurosci Lett,2007.424(1):p.27-30.
[23]Kuo, H.K., C.J. Yen, C.H. Chang, C.K. Kuo, J.H. Chen, and F. Sorond, Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population:systematic review and meta-analysis. Lancet Neurol, 2005.4(6):p.371-80.
[24]O'Bryant, S.E., S.C. Waring, V. Hobson, J.R. Hall, C.B. Moore, T. Bottiglieri, P. Massman, and R. Diaz-Arrastia, Decreased C-reactive protein levels in Alzheimer disease. J Geriatr Psychiatry Neurol.23(1):p.49-53.
[25]Van Oijen, M., M.P. de Maat, I. Kardys, F.J. de Jong, A. Hofman, P.J. Koudstaal, J.C. Witteman, and M.M. Breteler, Polymorphisms and haplotypes in the C-reactive protein gene and risk of dementia. Neurobiol Aging,2007. 28(9):p.1361-6.
[26]Iwamoto, N., E. Nishiyama, J. Ohwada, and H. Arai, Demonstration of CRP immunoreactivity in brains of Alzheimer's disease:immunohistochemical study using formic acid pretreatment of tissue sections. Neurosci Lett,1994. 177(1-2):p.23-6.
[27]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Human neurons generate C-reactive protein and amyloid P:upregulation in Alzheimer's disease. Brain Res,2000.887(1):p.80-9.
[28]Duong, T., P.J. Acton, and R.A. Johnson, The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions. Brain Res,1998. 813(2):p.303-12.
[29]McGeer, E.G., K. Yasojima, C. Schwab, and P.L. McGeer, The pentraxins: possible role in Alzheimer's disease and other innate inflammatory diseases. Neurobiol Aging,2001.22(6):p.843-8.
[30]Mielke, M.M., P.B. Rosenberg, J. Tschanz, L. Cook, C. Corcoran, K.M. Hayden, M. Norton, P.V. Rabins, R.C. Green, K.A. Welsh-Bohmer, J.C. Breitner, R. Munger, and C.G Lyketsos, Vascular factors predict rate of progression in Alzheimer disease. Neurology,2007.69(19):p.1850-8.
[31]Blaschke, F., D. Bruemmer, F. Yin, Y. Takata, W. Wang, M.C. Fishbein, T. Okura, J. Higaki, K. Graf, E. Fleck, W.A. Hsueh, and R.E. Law, C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation,2004.110(5):p.579-87.
[32]Grad, E., M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E.R. Edelman, and H.D. Danenberg, Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury. Am J Physiol Heart Circ Physiol,2007.293(1):p. H489-95.
[33]Zhang, J., Y.C. Rui, P.Y. Yang, L. Lu, and T.J. Li, C-reactive protein induced expression of adhesion molecules in cultured cerebral microvascular endothelial cells. Life Sci,2006.78(26):p.2983-8.
[34]Gill, R., J.A. Kemp, C. Sabin, and M.B. Pepys, Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats. J Cereb Blood Flow Metab,2004.24(11):p.1214-8.
[35]Nazarov, P.G, I.B. Krylova, N.R. Evdokimova, G.I. Nezhinskaya, and A.A. Butyugov, C-reactive protein:a pentraxin with anti-acetylcholine activity. Life Sci,2007.80(24-25):p.2337-41.
[36]Boekholdt, S.M. and J.J. Kastelein, C-reactive protein and cardiovascular risk: more fuel to the fire. Lancet.375(9709):p.95-6.
[37]Pepys, M.B., G.M. Hirschfield, GA. Tennent, J.R. Gallimore, M.C. Kahan, V. Bellotti, P.N. Hawkins, R.M. Myers, M.D. Smith, A. Polara, A.J. Cobb, S.V. Ley, J.A. Aquilina, C.V. Robinson, I. Sharif, GA. Gray, C.A. Sabin, M.C. Jenvey, S.E. Kolstoe, D. Thompson, and S.P. Wood, Targeting C-reactive protein for the treatment of cardiovascular disease. Nature,2006.440(7088):p. 1217-21.
[38]Kitsis, R.N. and I. Jialal, Limiting myocardial damage during acute myocardial infarction by inhibiting C-reactive protein. N Engl J Med,2006. 355(5):p.513-5.
[39]Raghavendra, V. and S.K. Kulkarni, Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks. Free Radic Biol Med,2001. 30(6):p.595-602.
[40]Affar, E.B., M. Germain, E. Winstall, M. Vodenicharov, R.G Shah, GS. Salvesen, and G.G. Poirier, Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. J Biol Chem,2001. 276(4):p.2935-42.
[41]Fezoui, Y. and D.B. Teplow, Kinetic studies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization. J Biol Chem,2002. 277(40):p.36948-54.
[42]Pallitto, M.M. and R.M. Murphy, A mathematical model of the kinetics of beta-amyloid fibril growth from the denatured state. Biophys J,2001.81(3):p. 1805-22.
[43]Parbhu, A., H. Lin, J. Thimm, and R. Lal, Imaging real-time aggregation of amyloid beta protein (1-42) by atomic force microscopy. Peptides,2002.23(7): p.1265-70.
[44]Serpell, L.C., Alzheimer's amyloid fibrils:structure and assembly. Biochim Biophys Acta,2000.1502(1):p.16-30.
[45]Walsh, D.M., A. Lomakin, G.B. Benedek, M.M. Condron, and D.B. Teplow, Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem,1997.272(35):p.22364-72.
[46]Yankner, B.A., L.K. Duffy, and D.A. Kirschner, Neurotrophic and neurotoxic effects of amyloid beta protein:reversal by tachykinin neuropeptides. Science, 1990.250(4978):p.279-82.
[47]Zheng, W.H., S. Bastianetto, F. Mennicken, W. Ma, and S. Kar, Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience,2002.115(1):p.201-11.
[48]Harkany, T., I. Abraham, C. Konya, C. Nyakas, M. Zarandi, B. Penke, and P.G. Luiten, Mechanisms of beta-amyloid neurotoxicity:perspectives of pharmacotherapy. Rev Neurosci,2000.11(4):p.329-82.
[49]Varadarajan, S., S. Yatin, M. Aksenova, and D.A. Butterfield, Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol,2000.130(2-3):p.184-208.
[50]Pike, C.J., A.J. Walencewicz-Wasserman, J. Kosmoski, D.H. Cribbs, C.G. Glabe, and C.W. Cotman, Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem,1995.64(1):p.253-65.
[51]Laczko, I., S. Holly, Z. Konya, K. Soos, J.L. Varga, M. Hollosi, and B. Penke, Conformational mapping of amyloid peptides from the putative neurotoxic 25-35 region. Biochem Biophys Res Commun,1994.205(1):p.120-6.
[52]Forloni, G, R. Chiesa, S. Smiroldo, L. Verga, M. Salmona, F. Tagliavini, and N. Angeretti, Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35. Neuroreport,1993.4(5):p. 523-6.
[53]Kim, H.S., C.H. Park, S.H. Cha, J.H. Lee, S. Lee, Y. Kim, J.C. Rah, S.J. Jeong, and Y.H. Suh, Carboxyl-terminal fragment of Alzheimer's APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity. FASEB J,2000.14(11):p.1508-17.
[54]Cheng, G., S.N. Whitehead, V. Hachinski, and D.F. Cechetto, Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis,2006.23(1):p. 140-51.
[55]Tohda, C., N. Matsumoto, K. Zou, M.R. Meselhy, and K. Komatsu, Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, A metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology,2004.29(5):p.860-8.
[56]Stepanichev, M.Y., I.M. Zdobnova, Zarubenko, Ⅱ, Y.V. Moiseeva, N.A. Lazareva, M.V. Onufriev, and N.V. Gulyaeva, Amyloid-beta(25-35)-induced memory impairments correlate with cell loss in rat hippocampus. Physiol Behav,2004.80(5):p.647-55.
[57]Albert, D.J. and G.L. Chew, The septal forebrain and the inhibitory modulation of attack and defense in the rat. A review. Behav Neural Biol, 1980.30(4):p.357-88.
[58]Gray, J.A. and N. McNaughton, Comparison between the behavioural effects of septal and hippocampal lesions:a review. Neurosci Biobehav Rev,1983. 7(2):p.119-88.
[59]Duong, T., M. Nikolaeva, and P.J. Acton, C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease. Brain Res,1997.749(1):p.152-6.
[60]Coughlan, C.M. and K.C. Breen, Factors influencing the processing and function of the amyloid beta precursor protein--a potential therapeutic target in Alzheimer's disease? Pharmacol Ther,2000.86(2):p.111-45.
[61]Stein, T.D., N.J. Anders, C. DeCarli, S.L. Chan, M.P. Mattson, and J.A. Johnson, Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons:support for the amyloid hypothesis. J Neurosci,2004.24(35):p.7707-17.
[62]Racchi, M. and S. Govoni, The pharmacology of amyloid precursor protein processing. Exp Gerontol,2003.38(1-2):p.145-57.
[63]Cappai, R. and A.R. White, Amyloid beta. Int J Biochem Cell Biol,1999. 31(9):p.885-9.
[64]Cole, S.L. and R. Vassar, BACE1 structure and function in health and Alzheimer's disease. Curr Alzheimer Res,2008.5(2):p.100-20.
[65]Golde, T.E. and S.G Younkin, Presenilins as therapeutic targets for the treatment of Alzheimer's disease. Trends Mol Med,2001.7(6):p.264-9.
[66]Octave, J.N., R. Essalmani, B. Tasiaux, J. Menager, C. Czech, and L. Mercken, The role of presenilin-1 in the gamma-secretase cleavage of the amyloid precursor protein of Alzheimer's disease. J Biol Chem,2000.275(3):p. 1525-8.
[67]Wolfe, M.S., W. Xia, B.L. Ostaszewski, T.S. Diehl, W.T. Kimberly, and D.J. Selkoe, Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature,1999.398(6727):p. 513-7.
[68]Klementiev, B., T. Novikova, V. Novitskaya, P.S. Walmod, O. Dmytriyeva, B. Pakkenberg, V. Berezin, and E. Bock, A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35. Neuroscience,2007.145(1):p.209-24.
[69]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Human neurons generate C-reactive protein and amyloid P:upregulation in Alzheimer's disease. Brain Research,2000.887(1):p.80-89.
[70]McGeer, P.L., E.G McGeer, and K. Yasojima, Alzheimer disease and neuroinflammation. J Neural Transm Suppl,2000.59:p.53-7.
[71]Greene, L.A. and A.S. Tischler, Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A,1976.73(7):p.2424-8.
[72]Schubert, D., S. Heinemann, and Y. Kidokoro, Cholinergic metabolism and synapse formation by a rat nerve cell line. Proc Natl Acad Sci U S A,1977. 74(6):p.2579-83.
[73]Dong, Q. and J.R. Wright, Expression of C-reactive protein by alveolar macrophages. J Immunol,1996.156(12):p.4815-20.
[74]Weinhold, B. and U. Ruther, Interleukin-6-dependent and-independent regulation of the human C-reactive protein gene. Biochem J,1997.327 (Pt 2): p.425-9.
[75]Volanakis, J.E. and A.J. Narkates, Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement. J Immunol,1981. 126(5):p.1820-5.
[76]Volanakis, J.E. and K.W. Wirtz, Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature,1979.281(5727):p.155-7.
[77]Du Clos, T.W., The interaction of C-reactive protein and serum amyloid P component with nuclear antigens. Mol Biol Rep,1996.23(3-4):p.253-60.
[78]Gabay, C. and I. Kushner, Acute-phase proteins and other systemic responses to inflammation. N Engl J Med,1999.340(6):p.448-54.
[79]Szalai, A.J., C-reactive protein (CRP) and autoimmune disease:facts and conjectures. Clin Dev Immunol,2004.11(3-4):p.221-6.
[80]Du Clos, T.W. and C. Mold, C-reactive protein:an activator of innate immunity and a modulator of adaptive immunity. Immunol Res,2004.30(3): p.261-77.
[81]Rogers, J. and L.F. Lue, Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int,2001.39(5-6):p.333-40.
[82]Yasojima, K., C. Schwab, E.G McGeer, and P.L. McGeer, Up-regulated production and activation of the complement system in Alzheimer's disease brain. Am J Pathol,1999.154(3):p.927-36.
[83]Weggen, S., M. Rogers, and J. Eriksen, NSAIDs:small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol Sci,2007.28(10):p.536-43.
[84]Szekely, C.A., T. Town, and P.P. Zandi, NSAIDs for the chemoprevention of Alzheimer's disease. Subcell Biochem,2007.42:p.229-48.
[85]in t'Veld, B.A., A. Ruitenberg, A. Hofman, L.J. Launer, C.M. van Duijn, T. Stijnen, M.M. Breteler, and B.H. Stricker, Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med,2001.345(21):p. 1515-21.
[86]Schultzberg, M., C. Lindberg, A.F. Aronsson, E. Hjorth, S.D. Spulber, and M. Oprica, Inflammation in the nervous system--physiological and pathophysiological aspects. Physiol Behav,2007.92(1-2):p.121-8.
[87]Griffin, W.S., J.A. Nicoll, L.M. Grimaldi, J.G Sheng, and R.E. Mrak, The pervasiveness of interleukin-1 in alzheimer pathogenesis:a role for specific polymorphisms in disease risk. Exp Gerontol,2000.35(4):p.481-7.
[88]Blasko, I., F. Marx, E. Steiner, T. Hartmann, and B. Grubeck-Loebenstein, TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J,1999.13(1):p.63-8.
[89]Del Bo, R., N. Angeretti, E. Lucca, M.G De Simoni, and G Forloni, Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and [beta]-amyloid production in cultures. Neuroscience Letters,1995.188(1):p. 70-74.
[90]Giovannini, M.G., C. Scali, C. Prosperi, A. Bellucci, M.G. Vannucchi, S. Rosi, G. Pepeu, and F. Casamenti, Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo:involvement of the p38MAPK pathway. Neurobiol Dis,2002.11(2):p.257-74.
[1]Affar, E.B., M. Germain, E. Winstall, M. Vodenicharov, R.G. Shah, G.S. Salvesen, and G.G. Poirier, Caspase-3-mediated processing of poly(ADP-ribose) glycohydrolase during apoptosis. J Biol Chem,2001. 276(4):p.2935-42.
[2]Barnham, K.J., G.D. Ciccotosto, A.K. Tickler, F.E. Ali, D.G Smith, N.A. Williamson, Y.H. Lam, D. Carrington, D. Tew, G Kocak, I. Volitakis, F. Separovic, C.J. Barrow, J.D. Wade, C.L. Masters, R.A. Cherny, C.C. Curtain, A.I. Bush, and R. Cappai, Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem,2003.278(44):p.42959-65.
[3]Haque, A., N.L. Banik, and S.K. Ray, New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer's disease: cathepsin inhibitors as potential therapeutics. CNS Neurol Disord Drug Targets,2008.7(3):p.270-7.
[4]Goto, M., T. Kimura, S. Hagio, K. Ueda, S. Kitajima, H. Tokunaga, and E. Sato, Neuropathological analysis of dementia in a Japanese leprosarium. Dementia,1995.6(3):p.157-61.
[5]Weggen, S., M. Rogers, and J. Eriksen, NSAIDs:small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol Sci,2007.28(10):p.536-43.
[6]Schultzberg, M., C. Lindberg, A.F. Aronsson, E. Hjorth, S.D. Spulber, and M. Oprica, Inflammation in the nervous system--physiological and pathophysiological aspects. Physiol Behav,2007.92(1-2):p.121-8.
[7]Griffin, W.S., J.A. Nicoll, L.M. Grimaldi, J.G Sheng, and R.E. Mrak, The pervasiveness of interleukin-1 in alzheimer pathogenesis:a role for specific polymorphisms in disease risk. Exp Gerontol,2000.35(4):p.481-7.
[8]Townsend, K.P. and D. Pratico, Novel therapeutic opportunities for Alzheimer's disease:focus on nonsteroidal anti-inflammatory drugs. FASEB J, 2005.19(12):p.1592-601.
[9]McGeer, P.L., M. Schulzer, and E.G McGeer, Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease:a review of 17 epidemiologic studies. Neurology,1996.47(2):p.425-32.
[10]Breitner, J.C., K.A. Welsh, M.J. Helms, P.C. Gaskell, B.A. Gau, A.D. Roses, M.A. Pericak-Vance, and A.M. Saunders, Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging,1995.16(4):p.523-30.
[11]Rogers, J.B., Neuroinflammation in Alzheimer's disease. Neurobiology of Aging,2000.21 (Supplement 1):p.208-208.
[12]Torreilles, F. and J. Touchon, Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease. Prog Neurobiol,2002.66(3):p. 191-203.
[13]Lahiri, D.K., Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene. J Mol Neurosci,2004.23(3):p.225-33.
[14]Pisalyaput, K. and A.J. Tenner, Complement component C1q inhibits beta-amyloid-and serum amyloid P-induced neurotoxicity via caspase-and calpain-independent mechanisms. J Neurochem,2008.104(3):p.696-707.
[15]Lacor, P.N., M.C. Buniel, P.W. Furlow, A.S. Clemente, P.T. Velasco, M. Wood, K.L. Viola, and W.L. Klein, Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci,2007.27(4):p.796-807.
[16]Czirr, E., S. Leuchtenberger, C. Dorner-Ciossek, A. Schneider, M. Jucker, E.H. Koo, C.U. Pietrzik, K. Baumann, and S. Weggen, Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations. J Biol Chem, 2007.282(34):p.24504-13.
[17]Kim, E.J., K.J. Kwon, J.Y. Park, S.H. Lee, C.H. Moon, and E.J. Baik, Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons:associated with iNOS and COX-2. Brain Res,2002.941(1-2):p.1-10.
[18]Jans, D.M., W. Martinet, M. Fillet, M.M. Kockx, M.P. Merville, H. Bult, A.G. Herman, and GR. De Meyer, Effect of non-steroidal anti-inflammatory drugs on amyloid-beta formation and macrophage activation after platelet phagocytosis. J Cardiovasc Pharmacol,2004.43(3):p.462-70.
[19]Cacquevel, M., N. Lebeurrier, S. Cheenne, and D. Vivien, Cytokines in neuroinflammation and Alzheimer's disease. Curr Drug Targets,2004.5(6):p. 529-34.
[20]McGeer, E.G and P.L. McGeer, Neuroinflammation in Alzheimer's Disease and Mild Cognitive Impairment:A Field in Its Infancy. J Alzheimers Dis, 2009.
[21]Ray, B. and D.K. Lahiri, Neuroinflammation in Alzheimer's disease:different molecular targets and potential therapeutic agents including curcumin. Curr Opin Pharmacol,2009.9(4):p.434-44.
[22]Venneti, S., C.A. Wiley, and J. Kofler, Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol,2009. 4(2):p.227-43.
[23]Sastre, M., I. Dewachter, S. Rossner, N. Bogdanovic, E. Rosen, P. Borghgraef, B.O. Evert, L. Dumitrescu-Ozimek, D.R. Thal, G Landreth, J. Walter, T. Klockgether, F. van Leuven, and M.T. Heneka, Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A,2006.103(2):p.443-8.
[24]Weggen, S., J.L. Eriksen, S.A. Sagi, C.U. Pietrzik, V. Ozols, A. Fauq, T.E. Golde, and E.H. Koo, Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem,2003.278(34):p.31831-7.
[25]Valerio, A., F. Boroni, M. Benarese, I. Sarnico, V. Ghisi, L.G Bresciani, M. Ferrario, G Borsani, P. Spano, and M. Pizzi, NF-kappaB pathway:a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci,2006.23(7):p.1711-20.
[26]Casoli, T., G. Di Stefano, B. Giorgetti, M. Balietti, R. Recchioni, F. Moroni, F. Marcheselli, G. Bernardini, P. Fattoretti, and C. Bertoni-Freddari, Platelet as a physiological model to investigate apoptotic mechanisms in Alzheimer beta-amyloid peptide production. Mech Ageing Dev,2008.129(3):p.154-62.
[27]Lee, S.Y, J.W. Lee, H. Lee, H.S. Yoo, Y.P. Yun, K.W. Oh, T.Y. Ha, and J.T. Hong, Inhibitory effect of green tea extract on beta-amyloid-induced PC 12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. Brain Res Mol Brain Res, 2005.140(1-2):p.45-54.
[28]Czirr, E. and S. Weggen, Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds. Neurodegener Dis,2006.3(4-5):p.298-304.
[29]Harkany, T., I. Abraham, C. Konya, C. Nyakas, M. Zarandi, B. Penke, and P.G. Luiten, Mechanisms of beta-amyloid neurotoxicity:perspectives of pharmacotherapy. Rev Neurosci,2000.11(4):p.329-82.
[30]Thomas, T., T.G. Nadackal, and K. Thomas, Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-beta aggregation. Neuroreport,2001. 12(15):p.3263-7.
[31]Agdeppa, E.D., V. Kepe, A. Petri, N. Satyamurthy, J. Liu, S.C. Huang, GW. Small, GM. Cole, and J.R. Barrio, In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer's brain using the positron emission tomography molecular imaging probe 2-(1-[6-[(2-[(18)F]fluoroethylXmethyl) amino]-2-naphthyl] ethylidene)malono nitrile. Neuroscience,2003.117(3):p.723-30.
[32]Dokmeci, D., Ibuprofen and Alzheimer's disease. Folia Med (Plovdiv),2004. 46(2):p.5-10.
[33]Schwarzman, A.L., L. Gregori, M.P. Vitek, S. Lyubski, W.J. Strittmatter, J.J. Enghilde, R. Bhasin, J. Silverman, K.H. Weisgraber, P.K. Coyle, and et al., Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci U S A,1994.91(18):p.8368-72.
[34]Ray, I., A. Chauhan, H.M. Wisniewski, J. Wegiel, K.S. Kim, and V.P. Chauhan, Binding of amyloid beta-protein to intracellular brain proteins in rat and human. Neurochem Res,1998.23(10):p.1277-82.
[35]Mazur-Kolecka, B., J. Frackowiak, and H.M. Wisniewski, Apolipoproteins E3 and E4 induce, and transthyretin prevents accumulation of the Alzheimer's beta-amyloid peptide in cultured vascular smooth muscle cells. Brain Res, 1995.698(1-2):p.217-22.
[36]Carro, E., J.L. Trejo, T. Gomez-Isla, D. LeRoith, and I. Torres-Aleman, Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med, 2002.8(12):p.1390-7.
[37]Sousa, J.C., I. Cardoso, F. Marques, M.J. Saraiva, and J.A. Palha, Transthyretin and Alzheimer's disease:where in the brain? Neurobiol Aging, 2007.28(5):p.713-8.
[38]Schultz, K., K. Nilsson, J.E. Nielsen, S.G Lindquist, L.E. Hjermind, B.B. Andersen, A. Wallin, C. Nilsson, and A. Petersen, Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors. Eur J Neurol,2009.
[39]Palha, J.A., P. Moreira, T. Wisniewski, B. Frangione, and M.J. Saraiva, Transthyretin gene in Alzheimer's disease patients. Neurosci Lett,1996. 204(3):p.212-4.
[40]Merched, A., J.M. Serot, S. Visvikis, D. Aguillon, G. Faure, and G. Siest, Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry. FEBS Lett, 1998.425(2):p.225-8.
[41]Skovronsky, D.M., V.M. Lee, and D. Pratico, Amyloid precursor protein and amyloid beta peptide in human platelets. Role of cyclooxygenase and protein kinase C. J Biol Chem,2001.276(20):p.17036-43.
[42]Kinouchi, T., Y. Ono, H. Sorimachi, S. Ishiura, and K. Suzuki, Arachidonate metabolites affect the secretion of an N-terminal fragment of Alzheimer's disease amyloid precursor protein. Biochem Biophys Res Commun,1995. 209(3):p.841-9.
[43]Lee, R.K. and R.J. Wurtman, Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors. Ann N Y Acad Sci, 2000.920:p.261-8.
[44]Gasparini, L., L. Rusconi, H. Xu, P. del Soldato, and E. Ongini, Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J Neurochem,2004.88(2):p.337-48.
[45]Weggen, S., J.L. Eriksen, P. Das, S.A. Sagi, R. Wang, C.U. Pietrzik, K.A. Findlay, T.E. Smith, M.P. Murphy, T. Bulter, D.E. Kang, N. Marquez-Sterling, T.E. Golde, and E.H. Koo, A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature,2001.414(6860):p.212-6.
[46]Avramovich, Y, T. Amit, and M.B. Youdim, Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J Biol Chem,2002.277(35):p.31466-73.
[47]Eriksen, J.L., S.A. Sagi, T.E. Smith, S. Weggen, P. Das, D.C. McLendon, V.V. Ozols, K.W. Jessing, K.H. Zavitz, E.H. Koo, and T.E. Golde, NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest,2003.112(3):p.440-9.
[48]Morihara, T., T. Chu, O. Ubeda, W. Beech, and G.M. Cole, Selective inhibition of Abeta42 production by NSAID R-enantiomers. J Neurochem,2002.83(4): p.1009-12.
[49]Takahashi, Y, I. Hayashi, Y Tominari, K. Rikimaru, Y Morohashi, T. Kan, H. Natsugari, T. Fukuyama, T. Tomita, and T. Iwatsubo, Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem,2003.278(20):p.18664-70.
[50]Jantzen, P.T., K.E. Connor, G DiCarlo, G.L. Wenk, J.L. Wallace, A.M. Rojiani, D. Coppola, D. Morgan, and M.N. Gordon, Microglial activation and beta-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci,2002.22(6):p.2246-54.
[51]Kalgutkar, A.S., B.C. Crews, S.W. Rowlinson, A.B. Marnett, K.R. Kozak, R.P. Remmel, and L.J. Marnett, Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors:facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci U S A, 2000.97(2):p.925-30.
[52]Lim, G.P., F. Yang, T. Chu, P. Chen, W. Beech, B. Teter, T. Tran, O. Ubeda, K.H. Ashe, S.A. Frautschy, and GM. Cole, Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci,2000.20(15):p.5709-14.
[53]Yan, Q., J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A.L. Biere, M. Citron, and G Landreth, Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci,2003.23(20):p.7504-9.
[54]Kukar, T., S. Prescott, J.L. Eriksen, V. Holloway, M.P. Murphy, E.H. Koo, T.E. Golde, and M.M. Nicolle, Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci,2007.8:p.54.
[55]Lim, G.R., F. Yang, T. Chu, E. Gahtan, O. Ubeda, W. Beech, J.B. Overmier, K. Hsiao-Ashec, S.A. Frautschy, and GM. Cole, Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging, 2001.22(6):p.983-91.
[56]Bard, F., C. Cannon, R. Barbour, R.L. Burke, D. Games, H. Grajeda, T. Guido, K. Hu, J. Huang, K. Johnson-Wood, K. Khan, D. Kholodenko, M. Lee, I. Lieberburg, R. Motter, M. Nguyen, F. Soriano, N. Vasquez, K. Weiss, B. Welch, P. Seubert, D. Schenk, and T. Yednock, Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med,2000. 6(8):p.916-9.
[57]Sung, S., H. Yang, K. Uryu, E.B. Lee, L. Zhao, D. Shineman, J.Q. Trojanowski, V.M. Lee, and D. Pratico, Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease. Am J Pathol,2004. 165(6):p.2197-206.
[58]Lee, D.W., M.W. Sung, S.W. Park, W.J. Seong, J.L. Roh, B. Park, D.S. Heo, and K.H. Kim, Increased cyclooxygenase-2 expression in human squamous cell carcinomas of the head and neck and inhibition of proliferation by nonsteroidal anti-inflammatory drugs. Anticancer Res,2002.22(4):p. 2089-96.
[59]Xiang, Z., L. Ho, S. Yemul, Z. Zhao, W. Qing, P. Pompl, K. Kelley, A. Dang, D. Teplow, and G.M. Pasinetti, Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr,2002.10(5-6):p.271-8.
[60]Soh, J.W. and I.B. Weinstein, Role of COX-independent targets of NSAIDs and related compounds in cancer prevention and treatment. Prog Exp Tumor Res,2003.37:p.261-85.
[61]Tegeder, I., J. Pfeilschifter, and G. Geisslinger, Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J,2001.15(12):p.2057-72.
[62]Jaradat, M.S., B. Wongsud, S. Phornchirasilp, S.M. Rangwala, G Shams, M. Sutton, K.J. Romstedt, D.J. Noonan, and D.R. Feller, Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H(2) synthases by ibuprofen, naproxen, and indomethacin. Biochem Pharmacol,2001.62(12):p.1587-95.
[63]Wick, M., G Hurteau, C. Dessev, D. Chan, M.W. Geraci, R.A. Winn, L.E. Heasley, and R.A. Nemenoff, Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth. Mol Pharmacol,2002.62(5):p.1207-14.
[64]Pang, L., M. Nie, L. Corbett, and A.J. Knox, Cyclooxygenase-2 expression by nonsteroidal anti-inflammatory drugs in human airway smooth muscle cells: role of peroxisome proliferator-activated receptors. J Immunol,2003.170(2): p.1043-51.
[65]Blasko, I., A. Apochal, G. Boeck, T. Hartmann, B. Grubeck-Loebenstein, and G Ransmayr, Ibuprofen decreases cytokine-induced amyloid beta production in neuronal cells. Neurobiol Dis,2001.8(6):p.1094-101.
[66]Zhou, Y., Y. Su, B. Li, F. Liu, J.W. Ryder, X. Wu, P.A. Gonzalez-DeWhitt, V. Gelfanova, J.E. Hale, P.C. May, S.M. Paul, and B. Ni, Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science,2003.302(5648):p.1215-7.
[67]Herrmann, C., C. Block, C. Geisen, K. Haas, C. Weber, G Winde, T. Moroy, and O. Muller, Sulindac sulfide inhibits Ras signaling. Oncogene,1998. 17(14):p.1769-76.
[68]Gala, M., R. Sun, and V.W. Yang, Inhibition of cell transformation by sulindac sulfide is confined to-specific oncogenic pathways. Cancer Lett,2002.175(1): p.89-94.