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

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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)