Gene Expression in Alzheimer's Disease

阿尔茨海默氏病的基因表达

• 批准号: 6855783
• 负责人: WALTER J LUKIW
• 金额: $ 23.77万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855783
• 关键词: AP1 protein; Alzheimer' s disease; PC12 cells; aging; cell senescence; gel mobility shift assay; gene deletion mutation; gene induction /repression; genetic promoter element; glucocorticoids; hippocampus; human tissue; interleukin 1; isozymes; luciferin monooxygenase; neocortex; neuritic plaques; neurofibrillary tangles; neuropharmacology; neuroprotectants; nuclear factor kappa beta; presenilin; prostaglandin endoperoxide synthase; western blottings

DESCRIPTION (Provided by applicant): Alzheimer's disease (AD) represents an insidious, progressive, neurodestructive process of the human brain clinically characterized by the deterioration of memory and higher cognitive function. Familial AD and the more prevalent sporadic AD share final common neuropathological features that include a presenilin-1 (PS1) mediated catabolism of b-amyloid precursor protein (BAPP) generating neurotoxic amyloid-beta (AB) peptides that are deposited as insoluble senile plaque (SP). AB peptides and SPs increase reactive oxygen species (ROS) production which, in turn, fuel the expression of brain genes that promote proinflammatory (PI) episodes and brain cell death. The appearance in both familial and sporadic AD brain of reactive astrocytes, activated microglia and PI cytokines such as interleukin-1 beta (IL-1 beta) associated with AB and SP suggests that AD brain may be in a chronic state of inflammation. Abundant data that NSAIDs may be effective in ameliorating AD progression further supports a PI component to AD etiopathology. The goal of this project is to clarify the contributions of two key PI gene signaling pathways in AD brain which culminate in excessive stimulation of the neuroinflammatory response: (a) the inducible oxidoreductase cyclooxygenase-2 (COX-2) gene, which encodes the prostaglandin synthase responsible for prostanoid and other PI mediator production and (b) the presenilin-1 (PS1) gene, which drives aberrant processing of BAPP to accelerate AB production, Inducible COX-2 and PS1 gene over expression can both be regarded as upstream PI signaling events centrally involved in AD pathophysiology. The generation of ROS by AB also activates the binding to promoter DNA of NF-kB, a potent PI transcription factor (TF). Thus, NF-kB-DNA binding, driving COX-2 and PS1 gene transcription represent pivotal activating forces for PI signaling. The COX-2 and PS1 genes (a) exhibit down-regulation during human brain development, (b) are both sharply up-regulated in AD hippocampus, (c) are co-induced by AB42+ IL-I beta] in cultured human brain cells and (d) share at least 9 DNA regulatory motifs in their immediate promoters, including multiple AP1-, HIF1-, NF-Kb and STAT1-DNA binding sites, suggesting correlated gene activation. Using human control and AD brain analysis, human neural cells in primary culture and COX-2- and PS1-promoter, luciferase-reporter transfection models, we propose to test the hypothesis that signaling factors including PI TFs are key in the control of COX-2-and PS1-transcription-mediated over-stimulation of PI pathways that fuel neuronal cell degeneration in AD brain.

描述（由申请人提供）：阿尔茨海默病（AD）代表一种 临床上是人类大脑的一种潜在的、渐进的、神经破坏性的过程 以记忆力衰退和认知功能增强为特征。 家族性AD和更普遍的散发性AD有最后的共同点， 包括早老素-1（PS1）介导的神经病理学特征 β-淀粉样蛋白前体蛋白（BAPP）的催化剂产生神经毒性 淀粉样蛋白-β（AB）肽沉积为不溶性老年斑（SP）。 AB肽和SP增加活性氧（ROS）的产生， 反过来，刺激大脑基因的表达，促进促炎（PI） 发作和脑细胞死亡在家族性和散发性AD中， 反应性星形胶质细胞，活化的小胶质细胞和PI细胞因子， 白细胞介素-1 β（IL-1 β）与AB和SP相关，提示AD脑 可能处于慢性炎症状态大量数据表明NSAID可能 有效改善AD进展进一步支持了AD的PI组分 病因病理学这个项目的目标是澄清两个贡献 AD大脑中的关键PI基因信号通路，其最终导致过度的 刺激神经炎症反应：（a）诱导型氧化还原酶 环氧合酶-2（考克斯-2）基因，其编码前列腺素合酶 负责前列腺素类和其它PI介体的产生，和（B） 早老素-1（PS1）基因，它驱动BAPP的异常加工， 诱导型考克斯-2和PS 1基因的过度表达， 被认为是AD中集中参与的上游PI信号传导事件 病理生理学通过AB产生ROS也激活与 NF-κ B启动子DNA，一种有效的PI转录因子（TF）。因此，NF-kB-DNA 结合、驱动考克斯-2和PS1基因转录是关键的激活因子 PI信号的力量。考克斯-2和PS1基因（a）表现出下调 在人类大脑发育过程中，（B）在AD中均显著上调 海马，（c）在培养人脑中由AB 42 + IL-1 β共同诱导 细胞和（d）在它们的直接表达中共享至少9个DNA调控基序， 启动子，包括多个AP 1-、HIF 1-、NF-Kb和STAT 1-DNA结合位点， 表明相关的基因激活。使用人类控制和AD大脑 分析，原代培养的人神经细胞和考克斯-2-和PS1-启动子， 在转移酶-报告基因转染模型中，我们提出检验以下假设： 包括PITFs在内的信号传导因子是控制考克斯-2和 PS1转录介导的PI通路的过度刺激， AD脑细胞变性。