"Role of CXCR2 in beta-amyloid Induced Neurodegeneration"

趋化因子在阿尔茨海默病患者的大脑中上调，并在淀粉样蛋白β 基于这些初步发现，我们提出以下假设：1）一些（如果 并非所有的）由反应性神经胶质细胞产生的趋化因子保护神经元免受淀粉样蛋白-B的毒性 通过激活同源趋化因子受体，2)启动的特定信号通路 趋化因子受体参与趋化因子受体介导的神经保护。3)化因子 在发炎的中枢神经系统中的受体变得组成性脱敏，由于过度刺激的中枢神经系统， 受体的过度趋化因子和兴奋性氨基酸产生的活化星形胶质细胞， 小胶质细胞，从而导致临床中趋化因子受体介导的神经保护作用减弱。 例如发生在阿尔茨海默病中的那些。我提出了以下具体目标来测试这些 假设目标1.为了确定CXCR 2是否参与了对淀粉样蛋白-b肽诱导的 在转基因小鼠中使用CXCR 2敲除小鼠和选择性CXCR 2拮抗剂的神经元死亡 过表达人突变型人淀粉样前体蛋白作为实验工具。目标二。以确定 CXCR 2信号通路参与受体介导的抗淀粉样蛋白-b的神经保护作用 肽诱导的神经元损伤。.为了检测谷氨酸和趋化因子诱导的 受体脱敏和受体复敏受损对CXCR 2过表达失败的影响 AD防止神经退行性变：我们将从我们的研究中得出几个重要的基本认识。 这些研究对于了解神经退行性变的发病机制具有重要意义。 疾病及其治疗中断或预防。首先，我们将阐明CXCR 2受体在 在体外和体内，利用互补的神经保护免受由b-淀粉样蛋白激活的通路的影响， 形态、功能和行为评估。第二，我们将测试假设， 与神经保护相关的信号传导通过与以下相关的机制被NMDA抵消： CXCR 2再循环的中断和受体对内源性趋化因子敏感性的再生 在病理环境中过量产生，为有效的治疗策略提供了证据。 AD和其他神经退行性疾病的干预。

Chemokines are up-regulated in the brain of Alzheimer's disease patients and are produced after amyloid-beta stimulation of glial cells.Based on these initial findings, we propose the following hypothesis: 1) some (if not all) chemokines produced by the reactive glial cells protect neurons against the toxicity of amyloid-b peptide through activation of the cognate chemokine receptors. 2) Specific signaling pathways initiated by the chemokine receptors are involved in the chemokine receptor-mediated neuroprotection. 3) Chemokine receptors in the inflamed CNS become constitutively desensitized due to the over-stimulation of the receptors by the excessive chemokines and excitatory amino acids produced by the activated astrocytes and microglial cells, thus resulting in attenuation of the chemokine receptor-mediated neuroprotection in clinical settings, such as those occuring in Alzheimer's disease. I propose the following specific aims to test these hypotheses. Aim 1. To determine whether CXCR2 is involved in the protection against amyloid-b peptide-induced neuronal death using CXCR2 knock-out mice and a selective CXCR2 antagonist in transgenic mice overexpressing human mutant human amyloid precursor protein as experimental tools. Aim 2. To determine the signaling pathways of CXCR2 involved in the receptor-mediated neuroprotection against amyloid-b peptide -induced neuronal damage. . To examine the contribution of glutamate- and chemokine-induced receptor desensitization and impairment of receptor resensitization to the failure of CXCR2 overexpression in AD to protect against neurodegeneration: Several important fundamental understandings will result from our studies, all of which have signficance for the understanding of the pathogenesis of neurodegenerative disease and its therapeutic interruption or prevention. First, we will clarify the role of the CXCR2 receptor in neuroprotection from pathways activated by b-Amyloid protein, in vitro and in vivo, utilizing complementary morphological, functional and behavioral assessments. Second, we will test the hypothesis that chemokinemediated signaling relevant for neuroprotection is counteracted by NMDA via mechanisms related to interruption of CXCR2 recycling and regeneration of receptor sensitivity to endogenous chemokines produced in excess in pathological settings, providing evidence for useful strategies for therapeutic intervention in AD and other neurodegenerative diseases.