A-BETA INFUSION INDUCED DEPOSITION, INFLAMMATION AND NEUROTOXICITY

强有力的遗传证据与家族性阿尔茨海默病（FAD）有关 突变增加淀粉样β蛋白（Abeta）的产生。一个主要 淀粉样蛋白级联假说的另一个问题是， 将增加Abeta产生的FAD基因放入APP转基因中， AD发病机制的小鼠模型，它们显示出广泛的淀粉样蛋白斑块， 但缺乏可量化的神经元损失， 神经保护策略存在问题。有人可能会假设- 诱导淀粉样蛋白沉积所需的APP表达，导致过度 神经保护性APP结构域的表达，以及对 内在的神经保护机制（Bcl-2，抗氧化防御，Abeta 降解系统等）或β-淀粉样蛋白在小鼠中不是非常有毒。 啮齿动物输注模型允许分离APP与Abeta效应， 有助于研究调节沉积的辅助因子和辅助因子， 因素在这个提议中，我们研究了脂蛋白介导的方法， 长期向大鼠脑实质输送Abeta， 导致广泛的扩散沉积以及神经毒性， 可量化的反应性神经胶质增生我们将使用此Abeta输注模型： (1)为了表征和比较脑室内共刺激的作用， 输注源自E3/3的富含Abeta和ApoE同种型的HDL， E4/4供体（Genetics Core）或已知胶质源性CNS载脂蛋白 载脂蛋白E亚型对A β沉积、神经毒性和 小胶质细胞激活。(2)为了确定大鼠神经元损伤是否 来自Aim 1的大脑和AD大脑（病理学核心）将更好地相关 小胶质细胞活化，可溶性Abeta水平或不溶性Abeta 程度. (3)为了研究是否抑制纤维形成或 弥漫性斑块的消退可以减少或增加A β诱导的 神经毒性和神经胶质增生。(4)为了测试补体的作用 激活Abet输注诱导的神经毒性和沉积， 用补体抑制剂处理的大鼠或C3敲除小鼠。(5)我们将 确定脑渗透性酚类抗氧化剂的相对作用 和甾体抗炎药对A β诱导的小胶质细胞 激活，神经胶质增生，神经毒性和Abeta沉积，比较 这些药物对目标4中使用的补体抑制剂的功效。

Strong genetic evidence links familial Alzheimer Disease (FAD) mutations to increased amyloid beta protein (Abeta) production. A major remaining problem for the amyloid cascade hypothesis is that when the FAD genes which increase Abeta production are put in APP transgenic mouse model for AD pathogenesis, they show extensive amyloid plaques, but lack quantifiable neuron loss, making their use in studying neuroprotective strategies problematic. One might hypothesize that over- expression of APP required to induce amyloid deposits, results in over- expression of neuroprotective APP domains as well as poorly understood intrinsic neuroprotective mechanisms (Bcl-2, antioxidant defenses, Abeta degradation systems etc) or that beta-amyloid is not very toxic in mice. Rodent infusion models allow separation of APP versus Abeta effects and facilitate investigation of co-factors that modulate deposition and co- factors. In this proposal we investigate a lipoprotein-mediated method of chronic delivery of Abeta to the brain parenchyma in rats that results in widespread diffuse deposits as well as neurotoxicity and quantifiable reactive gliosis. We will use this Abeta infusion model to: (1) To characterize and compare the effects of intraventricular co- infusion of Abeta and ApoE isoform enriched HDL derived from E3/3 AND E4/4 donors (Genetics Core) or known glia-derived, CNS apolipoprotein carriers (Apo E isoforms) on Abeta deposition, neurotoxicity and microglial activation. (2) To determine whether neuron damage in rat brains from Aim 1 and in AD brain (Pathology Core) will correlate better with microglial activation, soluble Abeta levels or insoluble Abeta levels. (3) To investigate whether inhibition of fibril formation or regression of diffuse plaques can decrease or increase Abeta-induced neurotoxicity and gliosis in vivo. (4) To test the role of complement activation in Abet infusion-induced neurotoxicity and deposition using rats treated with complement inhibitors or C3 knockout mice. (5) We will determine the relative effects of brain permeable phenolic anti-oxidants and steroidal anti-inflammatory agents on Abeta-induced microglial activation, gliosis, neurotoxicity and Abeta deposition, comparing the efficacy of these drugs to the complement inhibitors used in aim 4.