Antiapoptotic Activity of Alzheimer Abeta

阿尔茨海默病（AD）是一种使人衰弱的神经退行性疾病，其特征是神经元细胞丢失和蛋白质聚集体沉积。这些神经病理参数与神经元细胞体中许多氧化应激标志物的存在相关，表明氧化机制参与神经元细胞损失和/或蛋白质沉积。虽然导致这种氧化应激的活性氧（ROS）的来源尚不清楚，但大脑通过上调抗氧化防御系统(如：SOD1和谷胱甘肽过氧化物酶表达升高)。我们现在有三条证据表明阿尔茨海默病中增加的β生成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（超氧化物歧化酶）活性，其次，纳米摩尔浓度的Abeta阻断营养因子停用后神经元的凋亡，第三，ad患者大脑的Abeta淀粉样蛋白负担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ad影响的大脑神经元细胞体相比，淀粉样蛋白沉积物和神经原纤维缠结的氧化修饰较少。总之，这些令人信服的数据为阿尔茨海默病和头部创伤后增加的β生成提供了一个合理的生理学解释。我们假设，随着疾病的进展，神经元细胞、小胶质细胞和β淀粉样蛋白沉积物慢性过量产生过氧化氢，可能会压倒老化大脑的抗氧化防御系统，最终导致ROS促进细胞凋亡。因此，我们假设的新方面是认识到Abeta的产生可能是一种多营养拮抗形式，因此在“正常”条件下（即超氧化物浓度适度增加和/或高还原当量），Abeta可能具有生理目的，但在异常条件下（即高浓度的超氧化物和Abeta导致过量的过氧化氢/低还原当量）可能促进神经元细胞死亡。因此，拟议的研究将研究Abeta的产生作为氧化应激的一种补偿机制，它在本质上既是抗氧化的，也是抗凋亡的，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诱导神经元重新进入细胞周期作为导致细胞死亡的机制。

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.