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 突变导致淀粉样β蛋白(Abeta)产量增加。一位少校 淀粉样蛋白级联假说的剩余问题是，当 增加Abeta产量的FAD基因被放入APP转基因中 AD发病机制的小鼠模型，它们显示广泛的淀粉样斑块， 但缺乏可量化的神经元损失，将其用于研究 神经保护策略存在问题。有人可能会假设，过度- 诱导淀粉样蛋白沉积所需的APP的表达，导致过度 神经保护性APP结构域的表达以及知之甚少 内在神经保护机制(Bcl2、抗氧化剂防御、Abeta 降解系统等)，或者β-淀粉样蛋白对小鼠毒性不大。 啮齿动物输液模型允许分离APP和Abeta效应和 促进对调节沉积和共沉积的辅助因素的研究 各种因素。在这项建议中，我们研究了一种脂蛋白介导的方法。 将Abeta慢性递送到大鼠的脑实质 导致广泛的弥漫性沉积以及神经毒性和 可量化的反应性胶质化。我们将使用这种Abeta输液模型来： (1)评价和比较脑室内联合化疗的效果。 输注来自E3/3和ApoE的Abeta和ApoE亚型富集型高密度脂蛋白 E4/4供体(Genetics Core)或已知的神经胶质细胞来源的CNS载脂蛋白 载体(载脂蛋白E亚型)对Abeta沉积、神经毒性和 小胶质细胞激活。(2)测定大鼠神经细胞损伤程度 来自AIM 1的大脑和AD大脑(病理核心)将更好地关联 小胶质细胞激活时，可溶性Abeta水平或不溶性Abeta水平 级别。(3)研究是否抑制原纤维形成或 弥漫性斑块的消退可以减少或增加Abeta诱导的 体内的神经毒性和胶质细胞增多症。(4)检验补体的作用 活化在教唆输液所致神经毒性和沉积中的应用 用补体抑制剂治疗的大鼠或C3基因敲除小鼠。(5)我们会 测定脑透性酚类抗氧化剂的相对作用 和类固醇抗炎药对Abeta诱导的小胶质细胞的影响 激活、胶质增生、神经毒性和Abeta沉积，比较 这些药物对AIM 4中使用的补体抑制剂的疗效。

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.