Determining Therapeutic Efficacy of AGE in AD

描述(申请人提供)：基于这一事实，即源于APP的淀粉样变性处理而产生的A-β是阿尔茨海默病发病机制(包括炎症)中的一个关键事件，并且胆固醇稳态和胆碱能系统调节APP的处理，目前的阿尔茨海默氏症的治疗针对的是胆碱能增强[他克林、Aricept/Donezepil、Riva tigmine、Galantamin]；以及非类固醇抗炎药[阿司匹林、布洛芬、吲哚美辛]；COX-2抑制剂[Celebrex，Vioxx]。这些药物会产生严重的副作用，包括胃肠道出血、肝肾毒性、恶心，对携带ApoE基因1的患者无效。目前研究的药物包括黄嘌呤衍生物-丙戊茶碱和降胆固醇药物[HMG-CoA还原酶抑制剂-他汀类]。尽管一些他汀类药物被证明是抗淀粉样变性的，但由于他汀类药物的促炎性质，几乎没有他汀类药物的临床试验是非决定性的。在这方面，具有多效性、副作用最小的天然替代品(S)可能比副作用严重的单组分合成药物具有更大的治疗效益。一种这样的替代品是大蒜。陈化大蒜提取物(AGE)含有多种植物化学物质。S-烯丙基-半胱氨酸组分(SAC)对NFkAPPAB、TNFα、IL-1β3、20和iNOS/24有抑制作用。我们的初步数据显示，AGE以剂量依赖的方式降低Tg2576中的TNFα和IL-1β。AGE的SAC和二烯丙基二硫(DADS)成分是天然的HMG-CoA还原酶抑制剂34/46。我们的初步数据显示，在AIzheimer的跨基因模型(Tg2576)中，年龄减少了大脑淀粉样蛋白。此外，已知AGE是自由基清除剂，可增强抗氧化酶(SOD、过氧化氢酶和谷胱甘肽还原酶)3，抑制脂质过氧化，抑制A-β诱导的细胞凋亡，并改善加速衰老小鼠的记忆障碍。因此，AGE是一种天然的“非甾体抗炎药、他汀类药物、抗氧化剂和抗细胞凋亡剂”，是目前用于治疗阿尔茨海默氏症的许多单成分合成药物的组合。然而，年龄作为阿尔茨海默氏症治疗方法的有效性还没有被探索。本项目旨在确定阿尔茨海默病瑞典双突变(K670M/N671L)模型(Tg2576)中年龄的多效性效应。 假设：多效性自然替代AGE将预防或逆转Tg2576中的AD样病理并改善行为缺陷。 具体目标：[1]确定饮食年龄是否会促进Tg2576中的非淀粉样蛋白加工并减少先前存在的淀粉样蛋白负荷；[2]确定饮食年龄是否会减弱A-β诱导的Tg2576中的炎症级联反应；[3)确定饮食年龄是否会抑制Tg2576中的细胞凋亡；[4]确定饮食年龄是否会改善Tg2576中的海马区Morris水迷宫的性能。 意义：目前使用胆碱能增强剂和非类固醇抗炎药治疗AD是有限的，因为它们有副作用，并且不能改变疾病过程。如果成功，该项目将验证使用安全、自然耐受性好、成本效益高的替代草药疗法治疗AD。

DESCRIPTION (provided by applicant): Based on the fact that genesis of A-beta derived from amyloidogenic processing of APP is a key event in Alzheimer's pathogenesis including inflammation, and that cholesterol homeostasis and cholinergic system regulate APP processing, current Alzheimer's therapy targets cholinergic enhancement [Tacrine, Aricept/Donezepil, Rivastigmine, Galantamine]; and regulation of inflammation by NSAIDs [Aspirin, Ibuprofen, Indomethacin]; COX-2 inhibitors [Celebrex, Vioxx]. These drugs exert serious side effects including gastrointestinal bleeding, liver and renal toxicity, nausea, and are not effective with patients carrying ApoE gene 1. Current investigational drugs include Xanthine derivatives-Propentofylline and cholesterol-lowering agents [HMG-CoA reductase inhibitors-Statins]. Although some statins are shown to be anti-amyloidogenic, few clinical trials with statins are non-conclusive due to their proinflammatory nature/39. In this respect, natural alternative(s) with pleiotropic useful properties and with least adverse effects may provide greater therapeutic benefit over single-ingredient synthetic pharmaceutical drugs having serious side effects. One such alternative is garlic. Aged garlic extract (AGE) contains multipotent phytochemicals. S-Allyl-Cystein (SAC) component of AGE inhibits NFkAPPAB, TNFalpha, IL-1Beta 3, 20, and iNOS/24. Our preliminary data show that AGE reduced TNFalpha and IL-1Beta in Tg2576 in a dose-dependent manner. SAC and Diallyl disulfide (DADS) components of AGE are natural HMG-CoA reductase inhibitors 34/46. Our preliminary data show that AGE reduced cerebral amyloid in AIzheimer's transqenic model (Tg2576). In addition, AGE is known to be free-radical scavenger that enhances anti-oxidant enzymes (SOD, catalase and glutathione reductase) 3, inhibits lipid peroxidation 20, inhibits A-beta-induced apoptosis and improves memory deficits in senescence-accelerated mice. Thus, AGE is a natural "NSAID, Statin, anti-oxidant and anti-apoptotic agent"-a combination of many single-ingredient synthetic pharmaceutical drugs currently used for Alzheimer's therapy. However, the validity of AGE as Alzheimer's therapy has not been explored. This project is to determine pleiotropic effects of AGE in Alzheimer's Swedish double mutant (K670M/N671L) model (Tg2576). Hypothesis: Multi-potent natural alternative AGE will prevent or reverse AD-like pathology and ameliorate behavioral deficits in Tg2576. Specific Aims: [1] Determine if dietary AGE will promote non-amyloidogenic processing and reduce pre-existing amyloid burden in Tg2576; [2] Determine if dietary AGE will attenuate A-beta-induced inflammatory cascade in Tg2576; [3] Determine if dietary AGE will inhibit apoptosis in Tg2576; [4] Determine if dietary AGE will improve hippocampal-based Morris Water Maze performance in Tg2576. Significance: Current AD-treatment utilizing cholinergic enhancers and NSAIDs is limited due to their adverse side effects and do not modify the disease process. If successful, this project will validate the use of safe, naturally well-tolerated, cost-effective and alternative herbal pharmacotherapy for treating AD.