Delineation of physiological and pathological Cdk5 activity in learning and memory and actin-dependent dynamics of dendritic spines: A model for Alzheimer`s disease

阿尔茨海默病(AD)最早的临床表现是记忆力丧失。因此，阿尔茨海默病的任何治疗干预的成功将在很大程度上取决于其防止记忆丧失的能力。细胞周期蛋白依赖性激酶(CDK)5活性异常是由于CDK5激活剂p35被截短的p25蛋白裂解所致，与AD的发病有关。P25在AD患者脑内积聚，导致神经变性和神经纤维缠结形成。最近的研究表明，生理上的CDK5/p35活性是海马依赖的联想学习的重要调节因子。然而，到目前为止，p25的产生和认知之间的关系还没有得到解决。我将调查p25介导的CDK5活性的解除调节是否与恐惧和空间记忆的改变获得或记忆的丧失相一致。为此，我将使用在蔡教授的实验室中创造的过度表达前脑特异的、可诱导的人类p25蛋白(P25tg)的小鼠。此外，通过结合行为测试、分子和细胞生物学以及现代成像技术，我将检验生理CDK5活性调节肌动蛋白动力学对联想学习的响应，而联想学习反过来调节海马树突棘的生长、密度和运动。将在可诱导的p25tg小鼠中进行相应的实验，以描绘失调的生理CDK5活性的作用。(包含空格的字符：1523)

The earliest clinical manifestation of Alzheimer's disease (AD) is the loss of memory. Therefore the success of any therapeutic intervention in AD will significantly depend on its ability to prevent memory loss. Dysregulated cyclin dependent kinase (Cdk) 5 activity, that results from proteolytic cleavage of the Cdk5 activator p35 to the truncated p25 protein, has been implicated in the pathogenesis of AD. P25 accumulates in brain of AD patients, causes neurodegeneration and the forination of neurofibrally tangles. Recent data demonstrated that physiological Cdk5/p35 activity is an important regulator of hippocampus-dependent associative leaming. However, a correlation between p25 production and cognition has thus far, not been addressed. I will investigate if p25-mediated deregulation of Cdk5 activity coincides with altered acquisition of fear and spatial memoiies or loss of memories. For that I will employ mice over-expressing forebrain specific, inducible human p25 protein (p25tg) that have been created in Prof. Tsai's laboratory. Furtherinore, by combining behavior tests, molecular and cellular biology as well as modem imaging techniques I will test the hypothesis that physiological Cdk5 activity modulares actin dynamics in response to associative leaming which in turn, regulates the growth, density and motility of hippocampal dendritic spines. Corresponding experiments will be performed in the inducible p25tg mice in order to delineate the actions of dysregulated and physiologic Cdk5 activity. (Characters including spaces: 1523)