BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS

生物金属、氧化应激和 AB 淀粉样变性

• 批准号: 6697088
• 负责人: XUDONG HUANG
• 金额: $ 16.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697088
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; brain cell; chelating agents; copper; dietary supplements; disease /disorder model; genetically modified animals; homeostasis; hydrogen peroxide; immunocytochemistry; iron; laboratory mouse; metals; microdialysis; neurochemistry; neurofibrillary tangles; neurons; neurotoxicology; oxidative stress; thiamine deficiency; tissue /cell culture; western blottings; zinc

DESCRIPTION (From the Applicant's Abstract): Compelling evidence has indicated that dyshomeostasis of biometals (Fe, Cu, Zn) and oxidative stress are neurochemical factors that participate in Abeta amyloid pathology of AD. The candidates found in vitro that they could promote aggregation and oxidative modifications of Abeta peptides, and recent reports show that amyloid plaques in post-mortem brain tissue of AD are markedly enriched in these biometals. Conversely, removal of these metals with chelators from post-mortem AD brain specimen causes the Abeta amyloid plaques to dissolve. More recently, the candidates discovered that novel redox interactions between Abeta and Cu(II), and to a lesser extent, Fe(III), engender production of reduced metal ions, Cu(I) and Fe(II), and the consequent generation of reactive oxygen species (ROS)-hydrogen peroxide (H2O2) and hydroxyl radical (OH). These abnormal interactions may lead to the brain oxidation damage that is observed in AD. Moreover, studies have also shown that H2O2 mediates Abeta cellular toxicity, enhances cellular APP expression, and heightens Abeta production, implicating a vicious cycle between Abeta amyloidosis and oxidative stress. Hence, the candidates hypothesize: Dysregulation of biometals (Fe, Cu, and Zn) and oxidative stress potentiate AD pathology. To test the hypothesis, the applicants plan to: (i) assess the impact of dietary metal supplementation with Fe, Cu and Zn, as well as oxidative stress induced by the dietary thiamine deficiency, upon Abeta amyloid pathology and non-amyloid pathology using APP2576 mice; (ii) to evaluate effects of redox-activ Fe and Cu on Abeta neurotoxicity using primary neuronal culture; (iii) to determine cerebral H2O2 levels accompanying Abeta amyloidosis using in vivo microdialysis. These data will advance our understanding of in vivo biochemical roles of biometal dyshomeostasis and oxidative stress in AD pathology, and provide a firm scientific base for understanding the potential of metal chelation and antioxidant therapies for AD.

描述（来自申请人的摘要）：令人信服的证据表明， 生物金属（Fe、Cu、Zn）平衡失调和氧化应激是 参与AD的A β淀粉样蛋白病理的神经化学因子。的 候选人在体外发现，他们可以促进聚集和氧化 最近的报道表明，淀粉样蛋白斑块 在AD死后脑组织中明显富集这些生物金属。 相反，用螯合剂从死后AD脑中除去这些金属， 样本导致Abeta淀粉样蛋白斑块溶解。最近的 候选人发现Abeta和Cu（II）之间的新型氧化还原相互作用， 以及在较小程度上，Fe（III），产生还原的金属离子， Cu（I）和Fe（II），以及随之产生的活性氧 （ROS）-过氧化氢（H2 O2）和羟基自由基（OH）。这些异常 这些相互作用可能导致在AD中观察到的脑氧化损伤。 此外，研究还表明H2 O2介导Abeta细胞毒性， 增强细胞APP的表达，并提高Abeta的产生，这意味着 淀粉样变性和氧化应激之间的恶性循环。所以 候选人假设：生物金属（Fe，Cu和Zn）调节失调， 氧化应激增强AD病理。为了验证这一假设， 申请人计划：（i）评估膳食金属补充剂的影响， 铁、铜、锌以及硫胺素诱导的氧化应激 缺乏症，在Abeta淀粉样蛋白病理学和非淀粉样蛋白病理学中使用 APP 2576小鼠;（ii）评价氧化还原活性Fe和Cu对Abeta的影响 使用原代神经元培养的神经毒性;（iii）测定脑H2 O2 使用体内微透析检测伴随A β淀粉样变性的水平。这些数据 将促进我们对生物金属在体内生物化学作用的理解 AD病理学中的稳态异常和氧化应激，并提供了一个坚定的 了解金属螯合潜力的科学基础， 抗氧化剂治疗AD