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年将有多达1300万人受到影响。目前，还没有预防或治疗AD的治疗方法，在临床试验中测试的疾病改善化合物也不成功。这些挫折强调了确定可以有针对性地预防或治疗AD的新病理机制的紧迫性。两种病理过程与AD的发生和进展密切相关：炎症和氧化应激。虽然这些现象是复杂的，但它们产生反应性酮醛的常见分子种类。这些反应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（考克斯-1和考克斯-2）的酶活性增加而产生的，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，其破坏或修饰蛋白质功能、定位和聚集。我们以前已经证明，这些加合物，或levuglandins（LG），在AD患者的海马与AD的严重程度的Braak量表的水平。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速率和神经毒性。最近，我们已经鉴定了一类小分子，其可以以非常高的亲和力结合LG，而不抑制考克斯-1或考克斯-2活性，并阻断LG-加合到脑中的蛋白质。在AIM 1中，我们将测试LG清除剂的施用是否将以预防性方式起作用以延迟在斑块前AD小鼠中开始的记忆缺陷的发作。将通过液相色谱串联质谱法分析不同队列的LG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清除剂的施用是否会在已经具有认知缺陷、确定的斑块负荷、tau磷酸化和突触缺陷的衰老APPS小鼠中具有有益的治疗效果，这种情况类似于MCI或AD患者的情况。从这些研究中产生的数据将提供关键的概念验证，验证这种小分子清除剂在成熟和充分表征的临床前AD模型中的预防和治疗方法。这也将为开发旨在降低AD中活性醛水平的药物提供新的药理学靶点的证据。 公共卫生相关性：在这项提案中，我们将确定是否治疗AD小鼠与活性γ-酮醛的清除剂可以抑制脑中LG加合物的形成，降低抗体低聚物的水平，并防止年轻的preplaque AD小鼠的行为和突触缺陷的发作，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AD的新型药物靶点，并证明清除脑中的反应性醛可防止AD的良好建立的动物模型中行为缺陷的发展。

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.