Oxidized Lipoproteins in Neurodegeneration

描述(由申请人提供)：该提案验证了以下假设 氧化型脂蛋白通过作用于神经元直接诱导神经变性 间接地通过清道夫的机制激活小胶质细胞 感受器。氧化应激介导的神经细胞丢失已被证实 在神经退行性疾病中，包括阿尔茨海默病(AD)和中风。 活性氧物种(ROS)可增加脂质的快速氧化和 产生脂质过氧化的蛋白质和氧化蛋白质产物。一次 形成，这些氧化修饰的脂质和蛋白质可能是主要手段 从而引发ROS毒性。高密度脂蛋白(HDL) 中枢神经系统易受微量氧化修饰 金属、ROS和酶途径。初步数据显示， 氧化型高密度脂蛋白(OxHDL)对神经细胞的损伤作用及机制 体外激活小胶质细胞反应。这项建议的具体目的 1)验证高密度脂蛋白在体外诱导神经变性的假说 并在体内通过激活ROS。我们将描述神经元和小胶质细胞的特征。 通过激活氧化应激、钙和细胞凋亡来响应oxHDL值 小路。2)检验ox高密度脂蛋白通过相互作用发挥作用的假设 神经元和小胶质细胞上有清道夫受体。我们将检查细胞 表达清道夫受体(SR)的细胞株和分离的细胞 SR1基因失活小鼠对oxHDL的反应改变。3)测试 载脂蛋白E(ApoE)基因可能影响 氧化与神经元和小胶质细胞对ox高密度脂蛋白的反应。我们将隔离 APOE特定的高密度脂蛋白颗粒，并确定它们对氧化和 它们对神经退化的影响。4)检验氧化高密度脂蛋白的假设 而清道夫受体在AD大脑中以区域模式存在，与 有选择性的脆弱性。我们将检查从对照和AD中分离出来的高密度脂蛋白 脑的氧化状态及其与载脂蛋白E基因的关系。我们还将 检查SR和其他潜在相关分子的表达 氧化高密度脂蛋白在阿尔茨海默病大脑中的作用这些研究应该为以下方面提供见解 高密度脂蛋白和SR在中枢神经系统的正常功能及在AD发病机制中的作用。

DESCRIPTION (provided by applicant): This proposal tests the hypothesis that oxidized lipoproteins induce neurodegeneration directly by acting on neurons and indirectly by activating microglia through a mechanism involving scavenger receptors. Oxidative stress mediated neuronal cell loss has been demonstrated in neurodegenerative disorders including Alzheimer's disease (AD) and stroke. Reactive oxygen species (ROS) can increase the rapid oxidation of lipids and proteins generating lipid peroxidation and oxidized protein products. Once formed, these oxidatively modified lipids and proteins may be the primary means by which ROS toxicity is elicited. High-density lipoproteins (HDLs) in the central nervous system are vulnerable to oxidative modification by trace metals, ROS, and enzymatic pathways. Preliminary data demonstrate the detrimental effects of oxidized HDL (oxHDL) on neuronal cells and the activation of microglial response in vitro. The specific aims of this proposal are: 1) To test the hypothesis that HDL induces neurodegeneration both in vitro and in vivo by activating ROS. We will characterize the neuronal and microglial response to oxHDL by activating oxidative stress, calcium and apoptotic pathways. 2) To test the hypothesis that oxHDL functions through interaction with scavenger receptors on neuronal and microglial cells. We will examine cell lines expressing scavenger receptors (SR) and cells isolated from SRgene-inactivation mice for altered response to oxHDL. 3) To test the hypothesis that the apolipoprotein E (apoE) genotype may affect the level of oxidation and the neuronal and microglial response to oxHDL. We will isolate apoE-specific HDL particles and determine their susceptibility to oxidation and their effects on neurodegeneration. 4) To test the hypothesis that oxidized HDL and scavenger receptors are present in AD brain in a regional pattern related to selective vulnerability. We will examine HDL isolated from control and AD brain for oxidative status and the relationship to apoE genotype. We will also examine the expression of SR and other molecules potentially relevant to the effects of oxHDL in the AD brain. These studies should provide insights into the normal function of HDL and SR in the CNS and in the pathogenesis of AD.