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Cell Models for Alzheimer's disease (AD): Lipids and Related Signaling Pathways

阿尔茨海默病 (AD) 细胞模型：脂质和相关信号通路

基本信息

批准号：
8530657
负责人：
GRACE Y SUN
金额：
$ 12.41万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530657
关键词：
Cell Models Alzheimer disease AD

项目摘要

DESCRIPTION (provided by applicant): The major goal of this Program Project Grant (PPG) is to explore novel and under-studied pathways that contribute to Alzheimer's disease (AD). The decreased neuronal plasticity and cognitive memory loss found in people with AD is associated with chronic oxidative stress and increased production of neurotoxic oligomeric amyloid beta (A?) that cause release of cytokines and other molecules that promote neurodegeneration and chronic inflammation. We believe that devising methods to limit chronic effects of oxidative stress and oligomeric A? production would have profoundly positive consequences for AD patients. Based on promising results in the current grant period, we propose to better understand the mechanisms underlying the effects of oxidative stress and A? in neurons and glial cells, information that will lead to better treatments for prevention of neurodegeneration and chronic inflammation in the AD brain. We will investigate neuroprotective and pro-inflammatory pathways in neurons, glia and brain microvessels using cell and animal models of AD. Three projects will test the hypotheses that: (1) progression of AD involves expression and activation of the cPLA?/sPLA2/NADPH oxidase pathways to induce inflammatory responses in glial cells and impairment of neuronal functions; (2) chronic inflammation in AD is mediated by P2Y2 receptors (P2Y2Rs) for cytokine-like nucleotides in astrocytes and cerebral microvessels through transactivation of integrins and growth factor receptors, and P2Y2Rs mediate neuroprotective APP processing by a different pathway than inflammation; and (3) statins have both cholesterol-independent and -dependent mechanisms of action that are neuroprotective due to drug-induced transcriptional up-regulation of anti-apoptotic Bcl-2 by ET- 1/calcinurin/NFAT-dependent pathways and inhibition of Rac1 geranylgeranylation. Two cores will support the projects: (A) Administrative Core A will oversee progress on the PPG; (B) Cell, Molecular, and Animal Core B will provide standardized preparations of primary cell cultures and transfectants, and transgenic mice, prepare tissue sections, and perform immunohistochemical analyses, Laser Capture Microdissection, microarray screening of gene expression, and molecular biology assays. These collaborative studies should identify novel strategies to control chronic inflammation and neurodegeneration in AD.

描述（由申请人提供）：该计划项目资助（PPG）的主要目标是探索导致阿尔茨海默病（AD）的新的和未充分研究的途径。在AD患者中发现的神经元可塑性降低和认知记忆丧失与慢性氧化应激和神经毒性寡聚淀粉样蛋白β（A？）导致细胞因子和其他分子的释放，促进神经变性和慢性炎症。我们相信，设计方法来限制氧化应激和低聚A的慢性影响？生产将对AD患者产生深远的积极影响。基于在目前的资助期内有希望的结果，我们建议更好地了解氧化应激和A？在神经元和神经胶质细胞中，这些信息将导致更好的治疗方法，以预防AD大脑中的神经变性和慢性炎症。我们将使用AD的细胞和动物模型研究神经元、神经胶质和脑微血管中的神经保护和促炎通路。三个项目将检验以下假设：（1）AD的进展涉及cPLA的表达和激活？（2）AD的慢性炎症是由星形胶质细胞和脑微血管中的P2 Y2受体（P2 Y2 Rs）通过整合素和生长因子受体的反式激活介导的，P2 Y2 Rs通过与炎症不同的途径介导神经保护性APP加工;和（3）他汀类药物具有胆固醇非依赖性和胆固醇依赖性的作用机制，由于ET- 1/钙调磷酸酶/NFAT依赖性途径引起的抗凋亡Bcl-2的药物诱导转录上调和Rac 1香叶基香叶基化的抑制，这些作用机制具有神经保护作用。两个核心将支持这些项目：（A）行政核心A将监督PPG的进展;（B）细胞、分子和动物核心B将提供原代细胞培养物和转染子以及转基因小鼠的标准化制备，制备组织切片，并进行免疫组织化学分析、激光捕获显微切割、基因表达的微阵列筛选和分子生物学测定。这些合作研究应该确定新的策略来控制AD的慢性炎症和神经退行性变。

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phospholipases A2 and inflammatory responses in the central nervous system.

DOI：
10.1007/s12017-009-8092-z
发表时间：
2010-06
期刊：
NEUROMOLECULAR MEDICINE
影响因子：
3.5
作者：
Sun, Grace Y.;Shelat, Phullara B.;Jensen, Michael B.;He, Yan;Sun, Albert Y.;Simonyi, Agnes
通讯作者：
Simonyi, Agnes

Isoprenoids, small GTPases and Alzheimer's disease.

DOI：
10.1016/j.bbalip.2010.03.014
发表时间：
2010-08
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Hooff GP;Wood WG;Müller WE;Eckert GP
通讯作者：
Eckert GP

Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.

DOI：
10.1042/an20100025
发表时间：
2011-02-08
期刊：
ASN neuro
影响因子：
4.7
作者：
He Y;Cui J;Lee JC;Ding S;Chalimoniuk M;Simonyi A;Sun AY;Gu Z;Weisman GA;Wood WG;Sun GY
通讯作者：
Sun GY

Murine synaptosomal lipid raft protein and lipid composition are altered by expression of human apoE 3 and 4 and by increasing age