Preclinical Pharmacogenomics and Synaptic Biomarkers for Alzheimer's Disease

描述（由申请人提供）：该提案的广泛长期目标将解决推进阿尔茨海默病（AD）治疗和预防的主要障碍：1-药物基因组学，2-涉及发病机制的多效机制的分子靶向，3-识别预测药物疗效的生物标志物。尽管存在局限性，动物模型已经成为确定有前景的临床方法的基础，包括A¿疫苗和补充omega-3脂肪酸（特别是二十二碳六烯酸，DHA），但这些方法的成功可能取决于遗传风险（药物基因组学），如果启动得太晚，效果可能不强。多种药物（鸡尾酒）可以更好地针对导致AD的多效机制。在这篇文章中，我们将重点放在ApoE4上，这是AD的主要遗传风险因子。新出现的临床数据表明，对非甾体抗炎药、抗氧化剂（Hayden等人，2007；Szekely等人，2008）、DHA或鱼（Whalley等人，2008）和淀粉样蛋白疫苗（Salloway等人，2009）有不同的ApoE亚型依赖反应。这一建议填补了一个主要的知识空白，因为尽管ApoE4具有巨大的影响，但尚未开展临床前药物基因组学研究。我们将描述ApoE4对DHA治疗反应的影响，并确定是否可以通过将DHA与抗氧化剂a -脂酸盐（菠菜等蔬菜中发现）或姜黄根中的天然抗炎药物姜黄素结合来提高疗效，我们发现这一组合具有协同作用，并在APP和tau模型中显示出很大的益处，但尚未对ApoE亚型进行测试。为了克服这些障碍，我们利用一种新的动物模型来靶向替代人类ApoE （E2， E3和E4亚型）。这种新模型的优点是它在一年内具有突触丧失和认知障碍，使人们能够评估ApoE亚型依赖于治疗的影响。我们将被动A¿疫苗接种作为“阳性对照”进行测试，并进一步验证该模型，因为临床数据表明，只有在非ApoE4携带者中才有最佳疗效。目的1)确定ApoE4基因型对限制DHA保护的影响。目的2)确定有限的DHA疗效（特别是ApoE4携带者）是否通过脂酸盐、姜黄素或联合使用得到改善；目的3)确定ApoE亚型依赖的血浆生物标志物，我们的数据表明这些生物标志物反映了突触丧失；目的4)确定血浆生物标志物反应，预测治疗疗效，包括免疫治疗。创新包括鉴定新的替代生物标志物，改进对apoe4携带者的预防，以及适合研究apoe基因型治疗相互作用的动物模型的新特征。总之，我们通过药物基因组学解决了翻译领域进展的关键障碍，不仅挑战了规划未来阿尔茨海默病预防计划的现有范例，而且还确定了新的神经退行性依赖血浆生物标志物，这对于克服阿尔茨海默病预防试验终点不足至关重要。

DESCRIPTION (provided by applicant): This proposal's broad long-term objectives will address major obstacles to advancing therapeutics and prevention in Alzheimer disease (AD): 1-pharmacogenomics, 2-the molecular targeting of pleiotropic mechanisms implicated in pathogenesis and 3- identifying biomarkers predicting drug efficacy. Despite their limitations, animal models have been fundamental for identifying promising clinical approaches, including the A¿ vaccine and supplementation with omega-3 fatty acids (particularly docosahexaenoic acid, DHA), but success of these approaches may depend on genetic risk (pharmacogenomics) and efficacy may not be robust, if initiated too late. Multiple drugs (cocktails) better target the pleiotropic mechanisms contributing to AD. In this proposal, we focus on ApoE4, the major genetic risk factor for AD. Emerging clinical data suggest a differential ApoE isoform-dependent response to NSAIDs, antioxidants (Hayden et al., 2007; Szekely et al., 2008), DHA or fish (Whalley et al., 2008) and the amyloid vaccine (Salloway et al., 2009). This proposal fulfills a major knowledge gap since, despite the huge impact of ApoE4, preclinical pharmacogenomics studies have not been undertaken. We will characterize the impact of ApoE4 on treatment responses to DHA and determine whether efficacy can be improved by combining DHA with the antioxidant a lipoate (found in vegetables like spinach) or the natural anti-inflammatory drug curcurmin from turmeric root, a combination which we have found to work synergistically and has shown large benefits in APP and tau models, but not tested in relation to ApoE isoform. To overcome these obstacles, we utilize a novel animal model with targeted replacement for human ApoE (isoforms E2, E3 and E4). The advantages of this novel model are that it has synapse loss and cognitive impairment within one year, enabling one to evaluate ApoE isoform dependent effects on treatments. We test passive A¿ vaccination as a "positive control" and to further validate the model since clinical data suggests optimal efficacy only in non ApoE4 carriers. Aim 1) Determine the impact of ApoE4 genotype on limiting DHA protection. Aim 2) Determine if limited DHA efficacy (especially with ApoE4 carriers) is improved with lipoate, curcumin or the combination, Aim 3) Identify ApoE isoform-dependent plasma biomarkers that our data suggest reflect synaptic loss, Aim 4) Identify plasma biomarker responses, that predict treatment efficacy, including immunotherapy. Innovations include identification of novel surrogate biomarkers, improved prevention for ApoE4-carriers and the novel characterization of an animal model suitable for investigating ApoE-genotype treatment interaction. In summary, we address critical barriers to progress in the field of translation by addressing pharmacogenomics, not only challenging existing paradigms for planning future AD prevention programs, but also identifying novel neurodegenerative-dependent plasma biomarkers, essential to overcome inadequate endpoints for AD prevention trials.