Targeting protein adduction by reactive aldehydes in Alzheimer's disease

描述(由申请人提供)：目前约有450万美国人患有阿尔茨海默病(AD)，到2050年将有多达1300万人受到影响。目前，阿尔茨海默病尚无预防或治疗方法，临床试验中测试的疾病修饰化合物也未获成功。这些挫折突显了确定新的病理机制的紧迫性，这些机制可以有针对性地预防或治疗AD。两个病理过程与AD的发生和发展密切相关：炎症和氧化应激。虽然这些现象很复杂，但它们产生了一种常见的反应性酮醛的分子物种。这些反应性醛的产生要么是氧化应激引起的脂质过氧化，要么是环氧合酶(COX-1和COX-2)的酶活性增加所致，这两种酶都是在炎症状态下诱导的。重要的是，这些反应性醛形成稳定的共价加合物，破坏或改变蛋白质的功能、定位和聚集。我们之前已经证明，AD患者海马区的这些加合物或左旋糖苷(LGs)水平与AD的Braak分级相关。重要的是，在淀粉样蛋白b(Ab)多肽上形成LG加合物会增加其寡聚化和神经毒性。最近，我们发现了一类小分子，它们能以很高的亲和力与LGs结合，而不抑制COX-1或COX-2的活性，并能阻断LG与脑内蛋白质的加成作用。在目标1中，我们将测试服用LG清道夫是否会以预防性的方式延缓开始于斑块前期AD小鼠的记忆障碍的发生。不同的队列将用液相色谱质谱联用分析LGs水平、氧化损伤、抗体多肽水平和炎症标志物。在AIM 2中，我们将研究LG清道夫对已经有认知缺陷、斑块负荷、tau磷酸化和突触缺陷的老年APPS小鼠是否有有益的治疗效果，这种情况与MCI或AD患者相似。这些研究产生的数据将提供关键的概念证据，验证这种小分子清除剂在已建立的和具有良好特征的临床前AD模型中的预防和治疗方法。它还将为开发旨在降低AD中活性醛水平的药物提供新的药理学目标。 公共卫生相关性：在这项建议中，我们将确定用活性伽马酮醛的清除剂治疗AD小鼠是否可以抑制大脑中LG加合物的形成，降低抗体寡聚体的水平，防止年轻的斑块前AD小鼠出现行为和突触缺陷，并减轻老年AD小鼠的疾病严重程度。这些临床前研究的成功完成将验证一种治疗AD的新药靶点，并证明清除大脑中的活性醛可以防止在已建立的AD动物模型中发生行为缺陷。

DESCRIPTION (provided by applicant): Approximately 4.5 million Americans are affected by Alzheimer's disease (AD) today and up to 13 million will be affected by 2050. At present, there is no preventive or therapeutic treatment for AD, and disease-modifying compounds tested in clinical trials have been unsuccessful. These setbacks underscore the urgency of identifying novel pathological mechanisms that can be targeted to prevent or treat AD. Two pathologic processes are intimately associated with the development and progression of AD: inflammation and oxidative stress. Although these phenomena are complex, they generate a common molecular species of reactive keto-aldehydes. These reactive aldehydes are produced as a result of either lipid peroxidation associated with oxidative stress or through increased enzymatic activity of the cyclooxygenases (COX-1 and COX-2), both of which are induced in inflammatory states. Importantly, these reactive aldehydes form stable covalent adducts that disrupt or modify protein function, localization, and aggregation. We have previously demonstrated that levels of these adducts, or levuglandins (LGs), in hippocampus of AD patients correlate with the Braak scale of AD severity. Importantly, formation of LG adducts on amyloid b (Ab) peptide increases its rate of oligomerization and neurotoxicity. Recently, we have identified a class of small molecules that can bind to LGs with very high affinity, without inhibiting either COX-1 or COX-2 activity, and block LG-adduction to proteins in brain. In AIM 1, we will test whether administration of LG scavenger will act in a preventive manner to delay the onset of memory deficits that begin in pre-plaque AD mice. Separate cohorts will be analyzed for levels of LGs by liquid chromatography tandem mass spectrometry, oxidative damage, Ab peptide levels, and inflammatory markers. In AIM 2, we will investigate whether administration of LG scavenger will have a beneficial therapeutic effect in aging APPS mice that already have cognitive deficits, an established plaque load, tau phosphorylation, and synaptic deficits, a situation similar to that of the MCI or AD patient. Data generated from these studies will provide a critical proof of concept validating a preventive as well as therapeutic approach for this small molecule scavenger in a well-established and well-characterized pre-clinical AD model. It will also provide evidence for a new pharmacological target for development of drugs aimed at reducing levels of reactive aldehydes in AD. PUBLIC HEALTH RELEVANCE: In this proposal, we will determine whether treating AD mice with a scavenger of reactive gamma ketoaldehydes can inhibit formation of LG adducts in brain, reduce levels of Ab oligomers, and prevent onset of behavioral and synaptic deficits in young preplaque AD mice and attenuate disease severity in aging AD mice. Successful completion of these pre-clinical studies will validate a novel drug target for AD and demonstrate that scavenging reactive aldehydes in brain prevents development of behavioral deficits in a well established animal model of AD.