Nogo-A调控阿尔茨海默病Aβ代谢的分子机制

项目名称： Nogo-A调控阿尔茨海默病Aβ代谢的分子机制

项目编号： No.81202519

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 肖飞

作者单位： 暨南大学

项目金额： 23万元

中文摘要： 近年研究表明，外伤后抑制神经再生的Nogo-A与阿尔茨海默病（AD）的发病有联系，其作用仍不清楚。我们前期研究发现，Nogo-A上的活性片段激活Nogo-66受体(NgR),抑制皮质神经元突起生长并增加β淀粉样蛋白(Aβ)的生成。本研究拟采用Western blot、RNA干扰、免疫共沉淀等技术，进一步深入研究Nogo-A调控Aβ代谢的分子机制，重点解决：1)NgR激活后介导的信号途径。阐明其下游信号分子ROCK和蛋白激酶C对Aβ代谢的关键酶(分泌酶、脑啡肽酶等)的调节通路；2）竞争抑制途径。明确Nogo-A是否通过竞争抑制淀粉样蛋白前体(APP)与NgR的结合,促进APP水解而增加Aβ生成；3)Nogo-A对正常和AD模型鼠脑内 Aβ代谢、病理和行为学的影响，是否通过以上机制起作用。本研究将拓展Aβ代谢的调控途径及干预其过度生成提供新靶点，也为Nogo-A在AD发病中的作用提供实验依据。

中文关键词： Nogo-A；β-淀粉样蛋白；阿尔茨海默病；；

英文摘要： The Nogo-A is known to contribute to inhibiting the neurite regeneration of neurons after traumatic injuries. Recent evidences suggest that Nogo-A is involved in the pathology of Alzheimer's disease(AD) and there remains a need to determine it's exact effect and underlying mechanism.Our initial study found that the active fragment of the Nogo-A inhibited neurite outgrowth and increased amyloid β-protein(Aβ)secretion of cortical neurons by activating Nogo-66 receptor(NgR).Based on our research work,this study will further explore the mechanisms of Nogo-A regulates the metabolism of Aβ by using Western blot, RNA interference, co-immmunoprecipitation technology et al, focus on: 1)NgR activated signal trnasduction process, explolre the pathway of the downstream signaling molecules Rho-associated coiled coil-containing protein kinase（ROCK）and protein kinase C regulate key enzymes(secretase,neprilysin etc) of Aβ metabolism; 2)The competitive inhibition pathway of Aβ generation, Nogo-A inhibits the combination of amyloid β-protein precursor (APP) and NgR by bonding to NgR competitively,promotes the hydrolysis of APP which results in increased Aβ generation; 3) To study the effects of Nogo-A on Aβ metabolism, pathological and behavioral changes of normal and AD model mice and confirm whether the mechanisms are consiste

英文关键词： Nogo-A；Amyloid β-protein；Alzheimer's disease；；