Targeting protein adduction by reactive aldehydes in Alzheimer's disease

阿尔茨海默病中活性醛的靶向蛋白质加合

• 批准号: 8443807
• 负责人: Katrin I. Andreasson
• 金额: $ 22.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443807
• 关键词: Affect; Affinity; Aging; Aldehydes; Alzheimer' s Disease; Alzheimer' s disease model; American; Amines; Amyloid; Animal Model; Arachidonic Acids; Asses; Attenuated; Behavioral; Binding; Biological; Brain; Chronic; Clinical Trials; Cognitive; Cognitive deficits; Complex; Data; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Excision; Hippocampus (Brain); Impaired cognition; Inflammation; Inflammatory; Injury; Isoprostanes; Lipid Peroxidation; Lipid Peroxides; Lipids; Liquid Chromatography; Lysine; Measures; Mediating; Memory impairment; Molecular; Mus; Onset of illness; Outcome; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathologic Processes; Patients; Penetrance; Peptides; Post-Translational Protein Processing; Prevention; Preventive; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Reactive Oxygen Species; Severity of illness; Staging; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transgenic Organisms; Weight; adduct; age related; aged; cohort; crosslink; cyclooxygenase 1; drug development; improved; in vivo; inflammatory marker; ketoaldehyde; long term memory; network dysfunction; neurotoxic; neurotoxicity; novel; novel strategies; oxidation; oxidative damage; pre-clinical; preclinical study; prevent; protein folding; protein function; response; small molecule; tandem mass spectrometry; tau phosphorylation

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.

描述（由申请人提供）：目前大约有 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 万美国人受到影响。目前，还没有针对 AD 的预防或治疗方法，并且正在测试缓解疾病的化合物在临床试验中并未取得成功。这些挫折凸显了确定可预防或治疗 AD 的新病理机制的紧迫性。有两种病理过程与 AD 的发生和进展密切相关：炎症和氧化应激。尽管这些现象很复杂，但它们产生了反应性酮醛的常见分子种类。这些反应性醛的产生是由于与氧化应激相关的脂质过氧化或通过环氧合酶（COX-1和COX-2）的酶活性增加而产生的，这两种情况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，破坏或改变蛋白质功能、定位和聚集。我们之前已经证明，AD 患者海马中这些加合物或 levuglandins (LG) 的水平与 AD 严重程度的 Braak 量表相关。重要的是，淀粉样 b (Ab) 肽上 LG 加合物的形成会增加其寡聚化和神经毒性的速率。最近，我们发现了一类小分子，可以以非常高的亲和力与 LG 结合，而不抑制 COX-1 或 COX-2 活性，并阻止 LG 与脑中蛋白质的加合。在 AIM 1 中，我们将测试 LG 清除剂的施用是否会以预防性方式发挥作用，以延缓斑块前 AD 小鼠开始出现的记忆缺陷的发生。将通过液相色谱串联质谱法、氧化损伤、Ab 肽水平和炎症标志物分析单独队列的 LG 水平。在 AIM 2 中，我们将研究给予 LG 清除剂是否会对已经出现认知缺陷、斑块负荷、tau 磷酸化和突触缺陷（与 MCI 或 AD 类似的情况）的衰老 APPS 小鼠产生有益的治疗效果病人。这些研究产生的数据将提供关键的概念证明，在成熟且特征明确的临床前 AD 模型中验证这种小分子清除剂的预防和治疗方法。它还将为开发旨在降低 AD 中活性醛水平的药物的新药理学靶点提供证据。