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-发病机制中涉及的多效性机制的分子靶向，3-鉴定预测药物疗效的生物标志物。尽管有其局限性，动物模型一直是确定有前途的临床方法的基础，包括A ²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），如果启动太晚，疗效可能不强。多种药物（鸡尾酒）更好地靶向导致AD的多效性机制。在这项提案中，我们专注于AD的主要遗传危险因素ApoE 4。新出现的临床数据表明对NSAID、抗氧化剂的不同ApoE亚型依赖性应答（Hayden等人，2007; Szekely等人，2008）、DHA或鱼（沃利等人，2008）和淀粉样蛋白疫苗（Salloway等人，2009年）。该提案填补了一个主要的知识空白，因为尽管ApoE 4具有巨大的影响，但尚未进行临床前药物基因组学研究。我们将描述ApoE 4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 lipoate（在菠菜等蔬菜中发现）或来自姜黄根的天然抗炎药curcurmin组合来提高疗效，我们发现这种组合具有协同作用，并在APP和tau模型中显示出巨大的益处，但没有测试ApoE亚型。为了克服这些障碍，我们利用了一种新的动物模型，靶向替代人ApoE（亚型E2，E3和E4）。这种新模型的优点在于，它在一年内具有突触丧失和认知障碍，使得人们能够评估ApoE同种型对治疗的依赖性作用。我们测试被动A？为了进一步验证该模型，将疫苗接种作为“阳性对照”，因为临床数据表明仅在非ApoE 4携带者中具有最佳功效。目的1）确定ApoE 4基因型对限制DHA保护的影响。目的2）确定有限的DHA功效（特别是对于ApoE 4携带者）是否用硫辛酸、姜黄素或组合改善，目的3）鉴定我们的数据表明反映突触损失的ApoE亚型依赖性血浆生物标志物，目的4）鉴定预测治疗功效（包括免疫疗法）的血浆生物标志物应答。创新包括鉴定新的替代生物标志物，改善对ApoE 4携带者的预防，以及适用于研究ApoE基因型治疗相互作用的动物模型的新特征。总之，我们通过解决药物基因组学问题，解决了翻译领域进展的关键障碍，不仅挑战了规划未来AD预防计划的现有范例，而且还确定了新的神经退行性疾病依赖性血浆生物标志物，这对于克服AD预防试验终点不足至关重要。 公共卫生相关性：在开发具有成本效益的预防AD的安全实用方法方面存在重大障碍，这是美国的一项重大利益，因为除了阿尔茨海默病（AD）的巨大情感负担之外，其呈指数增长的发病率和流行率在国家和国际一级都构成了即将发生的灾难性经济负担;但具有讽刺意味的是，减少AD的经济负担要求我们必须首先支付预防试验的高额费用，即使是短期的预防试验（例如6年），每种药物也很容易达到2 500万至5 000万美元。另一个主要障碍是，临床数据表明，一些有希望和安全的治疗方法（例如膳食ω-3脂肪酸DHA）的成功似乎与ApoE基因型相关（药物基因组学），但基础科学迄今未能调查和阐明这些发现的原因，这限制了未来试验的成功。该提案试图通过改进候选干预测试范例来克服DHA和其他阿尔茨海默病预防方法的这些主要障碍，所述候选干预测试范例将人ApoE同种型并入AD模型中，以确定在ApoE 4载体中效果差的药物是否可以通过提供炎症和氧化损伤的额外靶向的安全鸡尾酒来改进（多效性），除了鉴定反映突触损伤并与记忆缺陷相关的敏感血浆生物标志物之外;这些生物标志物工具将非常有助于预测认知下降之前的前驱期期间的干预功效。

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. PUBLIC HEALTH RELEVANCE: There are major barriers to developing cost-effective safe practical ways of preventing AD, a vital US interest since, in addition to the enormous emotional burden of Alzheimer disease (AD), its exponentially growing incidence and prevalence present a pending catastrophic economic burden at both national and international levels; but ironically reducing the economic burden of AD demands that we must first pay high costs for prevention trials, that can easily reach from $25 to 50 million per drug for even a short prevention trial (e.g. 6 years). Another major obstacle is that clinical data, suggesting success with some of the promising and safe treatments (e.g. the dietary omega-3 fatty acid DHA) appears ApoE genotype-dependent (pharmacogenomic), but the basic science has so far failed to investigate and elucidate the reasons for these findings, contributing to limiting success of future trials. This proposal attempts to overcome these major obstacles for DHA and other Alzheimer prevention methods by improving candidate intervention testing paradigms that incorporate human ApoE isoforms into the AD models to determine whether drugs that are poorly efficacious in ApoE4 carriers can be improved by safe cocktails that provide additional targeting of inflammation and oxidative damage (pleiotropic), in addition to identifying sensitive plasma biomarkers reflecting synaptic damage and linked to memory deficits; these biomarker tools will be extremely helpful to predict intervention efficacy during the prodromal period prior to cognitive decline.