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损失和蛋白质聚集体沉积。这些神经病理学参数与神经元细胞体中多种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。尽管导致这种氧化应激的活性氧 (ROS) 来源尚未明确，但大脑通过上调抗氧化防御系统（例如增加 SOD1 和谷胱甘肽过氧化物酶的表达）来应对这种慢性氧化挑战。我们现在有三方面的证据表明，AD 中 Abeta 生成的增加也可能是对氧化应激的一种代偿反应，可防止神经元凋亡。首先，我们通过体外研究确定 Abeta 具有显着的抗氧化（超氧化物歧化酶）活性，其次，纳摩尔浓度的 Abeta 可以阻止营养因子撤除后神经元的凋亡，第三，受 AD 影响的大脑的 Abeta 淀粉样蛋白负荷与氧化应激标志物显着负相关。为了支持这些发现，我们发现，与受 AD 影响的大脑神经元的细胞体相比，淀粉样蛋白沉积物和神经原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 和头部外伤后 Abeta 生成增加提供了合理的生理学解释。我们推测，随着疾病的进展，神经元细胞、小胶质细胞和 Abeta 淀粉样蛋白沉积物长期过量产生过氧化氢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。因此，我们假设的新颖之处在于认识到Abeta的产生可能是多效拮抗作用的一种形式，其中Abeta在“正常”条件下（即超氧化物浓度适度增加和/或高还原当量）可能具有生理目的，但在异常条件下可能促进神经元细胞死亡（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）。因此，拟议的研究将检查 Abeta 的产生作为氧化应激的补偿机制，其本质上既具有抗氧化作用又具有抗凋亡作用，同时测试压倒性的氧化挑战是否会促进细胞凋亡。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。

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.