Antiapoptotic Activity of Alzheimer Abeta

阿尔茨海默病 Abeta 的抗凋亡活性

• 批准号: 6631585
• 负责人: Craig S Atwood
• 金额: $ 18.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631585
• 关键词: Alzheimer's disease; BCL2 gene /protein; Bax gene /protein; NAD(H) phosphate; adenosine triphosphate; aging; amyloid proteins; apoptosis; cell cycle proteins; cyclins; enzyme activity; genetically modified animals; glutathione peroxidase; hamsters; hydrogen peroxide; laboratory mouse; laboratory rat; metals; mitochondria; neurons; neurotrophic factors; oxidative stress; p53 gene /protein; protein kinase; superoxide dismutase

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is characterized by neuronal cell loss and the deposition of protein aggregates. These neuropathological parameters are correlated with the presence of numerous markers of oxidative stress in the cell bodies of neurons suggesting the involvement of oxidative mechanisms in neuronal cell loss and/or protein deposition. Although the sources of the reactive oxygen species (ROS) leading to this oxidative stress have not been clarified, the brain responds to this chronic oxidative challenge by upregulating antioxidant defense systems (eg. increasing SOD1 and glutathione peroxidase expression). We now have three lines of evidence indicating that the increased generation of Abeta in AD also may be a compensatory response to oxidative stress that prevents neuronal apoptosis. Firstly, we have determined from in vitro studies that Abeta has significant antioxidant (superoxide dismutase) activity, secondly, that nanomolar concentrations of Abeta block apoptosis of neurons following trophic factor withdrawal, and thirdly that the Abeta amyloid burden of the AD-affected brain is significantly negatively correlated with oxidative stress markers. In support of these findings, we find fewer oxidative modifications in amyloid deposits and neurofibrillary tangles compared with the cell bodies of the neurons of AD-affected brains. Together, these compelling data provide a plausible physiological explanation for the increased generation of Abeta in AD and following head trauma. We hypothesize that as the disease progresses, the chronic overproduction of hydrogen peroxide by neuronal cells, microglia and Abeta amyloid deposits may overwhelm the antioxidant defense systems of the aging brain with the end result that ROS promote the apoptotic demise. Thus, the novel aspect of our hypothesis is the recognition that Abeta generation may be a form of pleiotrophic antagonism, whereby Abeta may be physiologically purposive under "normal" conditions (i.e. moderately increased concentrations of superoxide and/or high reducing equivalents), but may promote neuronal cell death under abnormal conditions (i.e. high concentrations of superoxide and Abeta that lead to excess hydrogen peroxide/low reducing equivalents). The proposed studies will therefore examine the generation of Abeta as a compensatory mechanism to oxidative stress that is both antioxidant and anti-apoptotic in nature while testing whether overwhelming oxidative challenges promote apoptosis. We also will test whether oxidative stress induces neurons to re-enter the cell cycle as a mechanism leading to cell death.

阿尔茨海默病(AD)是一种以神经细胞丢失和蛋白质聚集体沉积为特征的衰弱的神经退行性疾病。这些神经病理参数与神经元胞体中大量氧化应激标志物的存在相关，提示氧化机制参与了神经元细胞丢失和/或蛋白质沉积。虽然导致这种氧化应激的活性氧物种(ROS)的来源还不清楚，但大脑通过上调抗氧化防御系统来应对这种慢性氧化挑战(例如。增加SOD1和谷胱甘肽过氧化物酶的表达)。我们现在有三条证据表明，AD中Abeta生成的增加也可能是对氧化应激的代偿反应，从而防止神经元凋亡。首先，我们从体外研究中确定了Abeta具有显著的抗氧化剂(超氧化物歧化酶)活性，其次，纳摩尔浓度的Abeta阻止了营养因子停用后神经元的凋亡，第三，AD脑中Abeta的淀粉样蛋白负荷与氧化应激标志物显著负相关。为了支持这些发现，我们发现，与受AD影响的大脑神经元的胞体相比，淀粉样蛋白沉积和神经纤维缠结中的氧化修饰较少。总之，这些令人信服的数据为AD和头部创伤后Abeta的生成增加提供了一个合理的生理学解释。我们推测，随着疾病的发展，神经细胞、小胶质细胞和Aβ淀粉样蛋白沉积产生的过氧化氢长期过量可能会压倒衰老大脑的抗氧化防御系统，最终导致ROS促进细胞凋亡的死亡。因此，我们的假设的新方面是认识到Abeta的产生可能是一种多营养拮抗的形式，从而Abeta在“正常”条件下(即适度增加的超氧化物浓度和/或高还原当量)可能是生理目的的，但在异常条件下(即高浓度的超氧化物和Abeta导致过多的过氧化氢/低还原当量)可能会促进神经细胞死亡。因此，拟议的研究将检验Abeta的产生作为氧化应激的一种补偿机制，在性质上既是抗氧化剂又是抗凋亡的，同时测试压倒性的氧化挑战是否促进细胞凋亡。我们还将测试氧化应激是否会诱导神经元重新进入细胞周期，作为导致细胞死亡的机制。

项目成果

Copper Induces Apoptosis of Neuroblastoma Cells Via Post-translational Regulation of the Expression of Bcl-2-family Proteins and the tx Mouse is a Better Model of Hepatic than Brain Cu Toxicity.

• 发表时间: 2008
• 期刊: International journal of clinical and experimental medicine
• 影响因子: 0.1
• 作者: Hsien W Chan;Tianbing Liu;G. Verdile;G. Bishop;Ryan J. Haasl;Mark A. Smith;George Perry;R. Martins;C. Atwood

Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression.

• DOI: 10.1677/joe.1.07047
• 发表时间: 2006-12
• 期刊: The Journal of endocrinology
• 作者: Andrea C. Wilson;M. S. Salamat;Ryan J. Haasl;K. Roche;A. Karande;S. V. Meethal;E. Terasawa;R. Bowen;C. Atwood;C. Atwood

Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans.

秀丽隐杆线虫中促性腺激素释放激素受体直系同源物的鉴定。

• DOI: 10.1186/1471-2148-6-103
• 发表时间: 2006
• 期刊: BMC evolutionary biology
• 影响因子: 3.4
• 作者: VadakkadathMeethal,Sivan;Gallego,MiguelJ;Haasl,RyanJ;Petras3rd,StephenJ;Sgro,Jean-Yves;Atwood,CraigS
• 通讯作者: Atwood,CraigS

Alzheimer's disease: the impact of age-related changes in reproductive hormones.

阿尔茨海默病：与年龄相关的生殖激素变化的影响。

• DOI: 10.1007/s00018-004-4380-4
• 发表时间: 2005
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Atwood,CS