Determining Therapeutic Efficacy of AGE in AD

描述（由申请人提供）：基于以下事实，即源自APP的淀粉样蛋白生成加工的A-β的生成是阿尔茨海默病发病机制（包括炎症）中的关键事件，并且胆固醇稳态和胆碱能系统调节APP加工，当前阿尔茨海默病治疗靶向胆碱能增强[他克林、安理申/多奈泽匹尔、卡巴拉汀、加兰他敏];以及通过NSAID [阿司匹林、依维柯、吲哚美辛];考克斯-2抑制剂[西乐葆、万络]调节炎症。这些药物会产生严重的副作用，包括胃肠道出血、肝和肾毒性、恶心，并且对携带ApoE基因1的患者无效。目前的研究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-他汀类药物]。尽管一些他汀类药物被证明具有抗淀粉样蛋白生成作用，但由于其促炎性质，很少有他汀类药物的临床试验是非决定性的/39。 在这方面，具有多效性有用特性和最少副作用的天然替代物可以提供比具有严重副作用的单一成分合成药物更大的治疗益处。其中一种替代品是大蒜。老化大蒜提取物（AGE）含有多能植物化学物质。AGE的S-烯丙基-半胱氨酸（SAC）组分抑制NF κ B、TNF α、IL-1 β 3、20和iNOS/24。我们的初步数据显示AGE以剂量依赖性方式降低Tg 2576中的TNF α和IL-1 β。AGE的SAC和二烯丙基二硫化物（DADS）组分是天然HMG-CoA还原酶抑制剂34/46。 我们的初步数据显示AGE减少了AIIB的转基因模型（Tg 2576）中的脑淀粉样蛋白。 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20、抑制A-β诱导的细胞凋亡并改善加速衰老小鼠的记忆缺陷。因此，AGE是一种天然的“NSAID，他汀类药物，抗氧化剂和抗凋亡剂”-目前用于阿尔茨海默氏症治疗的许多单一成分合成药物的组合。然而，AGE作为阿尔茨海默氏症治疗的有效性尚未被探索。本课题旨在研究AGE对阿尔茨海默病瑞典双突变体（K670 M/N671 L）模型（Tg 2576）的多效性作用。 假设：多能天然替代AGE将预防或逆转AD样病理并改善Tg 2576中的行为缺陷。 具体目标：[1]确定饮食AGE是否会促进Tg 2576中的非淀粉样蛋白生成加工并减少预先存在的淀粉样蛋白负荷; [2]确定饮食AGE是否会减弱Tg 2576中A-β诱导的炎症级联反应; [3]确定饮食AGE是否会抑制Tg 2576中的细胞凋亡; [4]确定饮食AGE是否会改善Tg 2576中基于坎贝尔的Morris水迷宫性能。 重要性：目前使用胆碱能增强剂和NSAID的AD治疗由于其不良副作用而受到限制，并且不能改变疾病过程。如果成功，该项目将验证使用安全，自然耐受性良好，具有成本效益和替代草药药物治疗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.