AAV-9介导的抑制肽在p25转基因小鼠中对CDK5/p25病理活性的特异抑制及其对阿尔茨海默病的防治研究

阿尔茨海默病病程呈进行性发展，无特效药物。CDK5/P35的活性保证了中枢神经系统发育、成熟和记忆功能。但病理因素刺激P35产生P25，CDK5/p25异常活性使TAU过磷酸化导致了该病的主要病理样改变。有研究报道CDK5的抑制剂或CDK5 siRNA在动物体内能有效的抑制CDK5/p25 活性，并能减少疾病动物的TAU磷酸化和病理改变，但对其它的 CDKs 或 CDK5/p35 的活性有副作用，限制了其应用。我们曾报道了p35衍生的两种肽（CIP和P5）能在神经元细胞中特异抑制 CDK5/p25 活性，并防止神经元细胞凋亡，且没有上述的副作用。本课题拟将通过重组腺相关病毒AAV-9表达系统在p25诱导表达的疾病鼠中表达CIP和P5，研究两种肽在体内对CDK5/p25特异抑制、TAU高磷酸化的抑制、预防细胞凋亡、改善病理样变化及促进记忆功能的作用。本研究将为抑制肽的靶向抑制治疗提供依据。

Alzheimer's disease (AD) is a progressive neurodegenerative disorder without efficient treatments. Cyclin-dependent kinase 5 (CDK5) /p35 activity is important for the developing and mature nervous system and memory. Under pathological stimulating, p35 is cleaved into p25. Pathological CDK5 /p25 activity has been hypothesized to contribute to the tau hyperphosporylation and formation of aberrant tau aggregates. CDK5 inhibitors or CDK5 RNA interference have indicated efficiently inhibition on CDK5/p25 activity and decreased the number of neurofibrillary tangles in AD mice. However, their side effects on other CDKs or physiologic CDK5/p35 activity have limited their potential clinical application. Previously we have demonstrated that two peptides (CIP and P5) truncated from p35 can specifically inhibit CDK5/p25 activity and prevent apoptosis in primary brain cultured cells. There is no effect on other CDKs or CDK5/p35 activity. In this study, we will use AAV-9 expressing system to deliver CIP and P5 in p25 transgenic AD mice. The specific inhibition of CDK5/p25 , prevention of TAU hyperphosphorylation ,apoptosis and AD like pathological change and improvement of memory will be evaluated. Our study will further validate our specific inhibiting peptides on the therapeutic targeting ameliorating tau pathology.