Oxidized Lipoproteins in Neurodegeneration

描述（由申请人提供）：本提案检验以下假设： 氧化型脂蛋白通过直接作用于神经元诱导神经变性 间接地通过清道夫机制激活小胶质细胞 受体。氧化应激介导的神经元细胞损失已被证明 在神经退行性疾病包括阿尔茨海默病（AD）和中风中。 活性氧（ROS）可以增加脂质的快速氧化， 产生脂质过氧化和氧化蛋白质产物的蛋白质。一旦 形成，这些氧化修饰的脂质和蛋白质可能是主要手段 由此引发ROS毒性。高密度脂蛋白（HDL）在 中枢神经系统易受痕量氧化修饰 金属、ROS和酶途径。初步数据显示， 氧化HDL（oxHDL）对神经细胞的有害作用， 体外激活小胶质细胞反应。本提案的具体目标 主要有：1）在体外实验中， 在体内通过激活ROS。我们将描述神经元和小胶质细胞 通过激活氧化应激、钙和凋亡对oxHDL的反应 途径。2)为了验证oxHDL通过相互作用发挥作用的假设， 神经元和小胶质细胞上的清道夫受体。我们将检查细胞 表达清道夫受体（SR）的细胞系和从 SR基因失活小鼠对oxHDL的反应改变。3)测试 假设载脂蛋白E（apoE）基因型可能影响 氧化以及神经元和小胶质细胞对oxHDL的反应。我们将隔离 apoE特异性HDL颗粒，并确定其对氧化的敏感性， 对神经退化的影响4)为了验证氧化HDL 和清道夫受体存在于AD脑中的区域模式相关 选择性的脆弱性。我们将检查从对照组和AD中分离的HDL 脑组织氧化状态及其与apoE基因型的关系。我们还将 检查SR和其他分子的表达可能与 oxHDL在AD脑中的作用。这些研究应该提供洞察力， HDL和SR在中枢神经系统中的正常功能以及在AD的发病机制中的作用。

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.