Targeting protein adduction by reactive aldehydes in Alzheimer's disease

描述（由申请人提供）：今天大约有450万美国人受到阿尔茨海默病（AD）的影响，到2050年将达到1300万。目前，还没有针对AD的预防性或治疗性治疗方法，在临床试验中测试的疾病改善化合物也没有成功。这些挫折强调了识别新的病理机制以预防或治疗AD的紧迫性。两种病理过程与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活性酮醛分子种类。这些活性醛是由于与氧化应激相关的脂质过氧化或通过环加氧酶（COX-1和COX-2）的酶活性增加而产生的，这两种酶活性都是在炎症状态下诱导的。重要的是，这些活性醛形成稳定的共价加合物，破坏或修饰蛋白质的功能、定位和聚集。我们之前已经证明，阿尔茨海默病患者海马体中这些加合物或左旋uglandins （LGs）的水平与阿尔茨海默病严重程度的Braak量表相关。重要的是，淀粉样蛋白b （Ab）肽上LG加合物的形成增加了其寡聚化率和神经毒性。最近，我们已经发现了一类小分子，它们可以以非常高的亲和力与LGs结合，而不抑制COX-1或COX-2的活性，并阻断LGs对大脑蛋白质的内聚。在AIM 1中，我们将测试LG清道夫是否会起到预防作用，延迟斑块前AD小鼠开始的记忆缺陷的发生。将通过液相色谱串联质谱法分析单独队列的LGs水平、氧化损伤、Ab肽水平和炎症标志物。在AIM 2中，我们将研究LG清除剂是否会对已经存在认知缺陷、斑块负荷、tau磷酸化和突触缺陷（类似于MCI或AD患者的情况）的衰老app小鼠产生有益的治疗效果。从这些研究中产生的数据将提供一个关键的概念证明，在一个完善的和具有良好特征的临床前AD模型中，这种小分子清道夫既可以预防也可以治疗。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靶点。

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.