Gene Expression in Alzheimer's Disease

阿尔茨海默氏病的基因表达

• 批准号: 7196144
• 负责人: WALTER J LUKIW
• 金额: $ 22.81万
• 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/7196144
• 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(申请人提供)：阿尔茨海默病(AD)代表一种 人脑临床上潜伏的、进行性的、神经破坏性的过程 以记忆力下降和较高的认知功能为特征。 家族性阿尔茨海默病和更为普遍的散发性阿尔茨海默病最终共有 包括早老素-1(PS1)介导的神经病理特征 β-淀粉样前体蛋白的分解代谢产生神经毒性 淀粉样β蛋白(AB)多肽，以不溶性老年斑(SP)的形式沉积。 AB肽和SPS增加了活性氧(ROS)的产生，在 反过来，刺激促进促炎(PI)的大脑基因的表达 发作和脑细胞死亡。家族性和散发性阿尔茨海默病 脑内反应性星形胶质细胞、激活的小胶质细胞和PI细胞因子 白介素1β(IL-1β)与AB和SP相关提示AD脑 可能处于慢性炎症状态。非甾体抗炎药可能存在的大量数据 有效改善AD进展进一步支持AD的PI组件 病因学。这个项目的目标是澄清两个方面的贡献 阿尔茨海默病大脑中关键的PI基因信号通路最终导致过度 神经炎性反应的刺激：(A)可诱导的氧化还原酶 环氧合酶-2(COX-2)基因，编码前列腺素合成酶 负责前列腺素和其他PI调节剂的生产和(B) 早老素-1(PS1)基因，驱动BAPP异常加工加速 AB产生、诱导性COX-2和PS1基因的过度表达均可 被认为是集中参与AD的上游PI信号事件 病理生理学。AB产生的ROS也激活了与 核因子-kB的启动子DNA，一种有效的PI转录因子(Tf)。因此，核因子-kB-DNA 结合、驱动COX-2和PS1基因转录是关键的激活 PI信号的作用力。COX-2和PS1基因(A)表达下调 在人脑发育过程中，(B)和(B)在阿尔茨海默病中都急剧上调 (C)在培养的人脑中由AB42+IL-Iβ共同诱导的海马区 细胞和(D)至少有9个DNA调控基序在其直接 启动子，包括多个AP1-、HIF1-、NF-KB和STAT1-DNA结合位点， 暗示了相关基因的激活。使用人类控制和AD大脑 分析，原代培养的人神经细胞和COX-2和PS1-启动子， 荧光素酶-报告基因转染模型中，我们建议检验以下假设 包括PI、TF在内的信号转导因子是控制COX-2和 PS1转录介导的PI通路过度刺激为神经元提供能量 阿尔茨海默病脑内细胞变性。

项目成果

Antagonism of NF-κB-up-regulated micro RNAs (miRNAs) in sporadic Alzheimer's disease (AD)-anti-NF-κB vs. anti-miRNA strategies.

NF-κB-UP调节的微RNA（miRNA）在散发性阿尔茨海默氏病（AD）-ANTI-NF-κB与抗MIRNA策略中的拮抗作用。

• DOI: 10.3389/fgene.2013.00077
• 发表时间: 2013
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Lukiw WJ

Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells.

• DOI: 10.3233/jad-2005-8204
• 发表时间: 2005
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: P. Alexandrov;Yuhai Zhao;A. Pogue;M. Tarr;T. Kruck;M. Percy;J. Cui;W. Lukiw

Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line.

• DOI: 10.1016/j.jinorgbio.2013.05.010
• 发表时间: 2013-11
• 期刊: JOURNAL OF INORGANIC BIOCHEMISTRY
• 影响因子: 3.9
• 作者: Alexandrov, Peter N.;Zhao, Yuhai;Jones, Brandon M.;Bhattacharjee, Surjyadipta;Lukiw, Walter J.
• 通讯作者: Lukiw, Walter J.

Alteration of Biomolecular Conformation by Aluminum-Implications for Protein Misfolding Disease.

• DOI: 10.3390/molecules27165123
• 发表时间: 2022-08-11
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Zhao, Yuhai;Pogue, Aileen, I;Alexandrov, Peter N.;Butler, Leslie G.;Li, Wenhong;Jaber, Vivian R.;Lukiw, Walter J.
• 通讯作者: Lukiw, Walter J.

Metal-sulfate induced generation of ROS in human brain cells: detection using an isomeric mixture of 5- and 6-carboxy-2',7'-dichlorofluorescein diacetate (carboxy-DCFDA) as a cell permeant tracer.

• DOI: 10.3390/ijms13089615
• 发表时间: 2012
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Pogue AI;Jones BM;Bhattacharjee S;Percy ME;Zhao Y;Lukiw WJ
• 通讯作者: Lukiw WJ