Cell Models for AD: Lipids and Related Signaling Pathways

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。我们认为，设计方法来限制慢性氧化应激和寡聚体A？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。 相关性：痴呆症是一种严重影响人进行日常活动能力的大脑疾病。老年人中最常见的痴呆症是阿尔茨海默病（AD），它最初涉及大脑控制思维，记忆和语言的部分。多达450万美国人患有无法治愈的AD。

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. RELEVANCE: Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. The most common form of dementia among older people is Alzheimer's disease (AD), which initially involves the parts of the brain that control thought, memory, and language. Up to 4.5 million Americans suffer from AD from which there is no cure.