BALANCED BIOACTIVITY OF ALZHEIMER BETA AMYLOID PRECURSOR

描述(摘要)：越来越多的证据指出炎症的作用 阿尔茨海默氏症。数据还表明，β-淀粉样蛋白的代谢物 阿尔茨海默病病因学中的前体蛋白(β-APP)。我们 此前已经证明，分泌形式的贝塔应用程序(Sapp)可以保护 神经元可以抵抗几种有毒的侮辱。然而，我们最近确定， SAPP可以刺激小胶质细胞的促炎过程，小胶质细胞是一种单核细胞，在 大脑。有趣的是，SAPP的这两种截然不同的生物活性可以 受遗传和生化决定因素的差异调节，包括一种 与载脂蛋白E(ApoE)的物理作用。这些数据表明， SAPP对神经元活性和功能的最终影响假说 其神经保护和促炎作用的整合结果 活动，而这些活动的平衡取决于萨普结构 与载脂蛋白E的变化和相互作用。这一假说将通过 以下目标：1)描述载脂蛋白E和 Sapp；2)确定Sapp通过的信号转导机制 激活小胶质细胞中的炎症事件3)确定结构元素 负责APP的促炎活动；4F)确定各种 SAPP的活动最终与神经元功能有关 和生存。将采用多种方法。溶液结合分析 将被用来测量Sapp对各种ApoE亚型的亲和力。 小胶质细胞的激活将通过亚硝酸盐产生的分析来测量， 细胞因子表达和神经毒性。这些端点将应用于 SAPP信号转导机制的药理学测试，这将是 辅以对这些信号的激活进行生化测试 转导通路。基因突变和定点突变将被用于 描述SAPP促炎活性的结构决定因素，以便 可以将它们与ApoE结合和相关信号转导所需的那些进行比较 事件。神经元-小胶质细胞共培养和其他独特的培养系统将 用来确定战略行动计划活动的最终相互作用 神经元存活和突触完整性，以及通过 分子结构问题。这些研究可能揭示出一个关键组成部分 阿尔茨海默病的发病机制，解释现有炎症性疾病的含义 参与阿尔茨海默氏症，并提出针对以下方面的治疗策略 正在修改Sapp的操作。具体地说，阐明了细胞 Sapp激活小胶质细胞的机制可能为 阿尔茨海默病的治疗干预。

DESCRIPTION (Abstract): Increasing evidence points to a role for inflammation in Alzheimer's disease. Data also implicate metabolites of the beta-amyloid precursor protein (beta-APP) in the etiology of Alzheimer's disease. We previously have demonstrated that secreted forms of beta-APP (sAPP) protect neurons against several toxic insults. However, we recently determined that sAPP can stimulate proinflammatory processes in microglia, a monocytic cell in the brain. Interestingly, these two distinct bioactivities of sAPP can be differentially modulated by genetic and biochemical determinants, including a physical interaction with apolipoprotein E (ApoE). These data suggest the hypothesis that the ultimate effect of sAPP on neuronal viability and function results from the integration of its neuroprotective and proinflammatory activities, and that the balance of these activates depends on sAPP structural variations and interactions with ApoE. The hypothesis will be tested through the following objectives: 1) Characterize the interaction between ApoE and sAPP; 2) Determine the signal transduction mechanisms through which sAPP activates inflammatory events in microglia 3) Determine the structural elements responsible for APP's proinflammatory activity; 4F) Determine how various activities of sAPP are ultimately integrated with respect to neuronal function and survival. A diversity of methods will be applied. Solution binding assays will be used to measure the affinity of sAPP for various ApoE isoforms. Microglial activation will be measured through assays of nitrite production, cytokine expression, and neurotoxicity. These endpoints will be applied to pharmacological tests of sAPP signal transduction mechanisms, which will be complemented by biochemical tests of the activation of these signal transduction pathways. Deletional and site-specific mutagenesis will be used to delineate the structural determinants of sAPP proinflammatory activity so that they can be compared to those required for ApoE binding and relevant signaling events. Neuron-microglia co-cultures and other unique culture systems will be utilized to determine the ultimate interaction of sAPP activities at the level of neuronal survival and synaptic integrity, and its modulation by molecular-structure issues. These studies may reveal a key component of Alzheimer's pathogenesis, explain existing implications of inflammatory involvement in Alzheimer's, and suggest therapeutic strategies directed at modifying the actions of sAPP. Specifically, elucidation of the cellular mechanisms through which sAPP activates microglia may provide targets for therapeutic intervention in Alzheimer's disease.