Antiapoptotic Activity of Alzheimer Abeta

阿尔茨海默病 Abeta 的抗凋亡活性

基本信息

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
项目类别：
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

项目摘要

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.

阿尔茨海默氏病（AD）是一种令人衰弱的神经退行性疾病，其特征是神经元细胞丧失和蛋白质骨料的沉积。这些神经病理学参数与神经元细胞体中许多氧化应激的存在相关，这表明氧化机制参与神经元细胞损失和/或蛋白质沉积。尽管尚未阐明导致这种氧化应激的活性氧（ROS）的来源，但大脑通过上调抗氧化剂防御系统（例如增加SOD1和SOD1和谷胱甘肽过氧化物酶表达）来应对这种慢性氧化挑战。现在，我们有三条证据表明，AD中ABETA的产生增加也可能是对氧化应激的补偿性反应，以防止神经元细胞凋亡。首先，我们从体外研究中确定了Abeta具有明显的抗氧化剂（超氧化物歧化酶）活性，其次，撤消营养因子后，Abeta阻断神经元的纳摩尔浓度凋亡，第三，第三，ABETA ABETA杏仁体负担显着地与氧化应激分标具有显着的负相关。为了支持这些发现，我们发现与受广告影响大脑的神经元的细胞体相比，淀粉样蛋白沉积物和神经原纤维缠结的氧化修饰更少。这些引人注目的数据共同提供了合理的生理解释，以增加AD和头部创伤后ABETA产生的产生。我们假设随着疾病的发展，神经元细胞，小胶质细胞和Abeta淀粉样蛋白沉积物对过氧化氢的慢性过量生产可能会使衰老大脑的抗氧化剂防御系统淹没，最终会导致ROS促进凋亡的危险性。因此，我们假设的新方面是认识到Abeta产生可能是多生型拮抗作用的一种形式，在“正常”条件下，Abeta在生理上可能具有目的性，即超氧化物和/或高还原等效量的适度升高，但可能会促进过度浓度高度（均为超级浓度）。过氧化物/低还原等效物）。因此，拟议的研究将研究ABETA的产生是氧化应激的补偿机制，氧化应激本质上是抗氧化和抗凋亡的，同时测试了压倒性的氧化挑战是否会促进凋亡。我们还将测试氧化应激是否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

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

DOI：
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
通讯作者：
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
影响因子：
0
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
通讯作者：
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。