Cyclin-dependent kinase 5 (Cdk5) is a multifaceted protein serine/threonine kinase with recently described roles in the pathogenesis of a number of neurological disorders, the best-characterized being Alzheimer's disease (AD). Aberrant Cdk5 activity has also been implicated in other neurological disorders, including Neiman Pick's Type C disease and ischemic brain injury. Two related neuron-specific proteins, p35 and 39, have been identified that activate Cdk5 upon direct binding. In the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development including neuronal migration, axon, and dendrite development. Emerging evidence indicates pivotal roles for Cdk5 in synaptic plasticity, behavior, and cognition. Paradoxically, dysregulation of Cdk5 activity due to conversion of p35 to p25 by calpain is implicated in neurotoxicity and neurodegenerative diseases. The inducible p25 transgenic mice (CK-p25 Tg) exhibit hallmarks of AD including profound neuronal loss, reactive astrogliosis, tau pathology, and elevated beta- amyloid (Ab) peptides. In the past grant period, we made the unexpected finding that, while chronic p25 overexpression causes neurodegeneration and impaired synaptic plasticity, acute p25 overexpression in the CK-p25 mice enhances synaptic plasticity and facilitates learning and memory. This led us to the hypothesis that p25 has a physiological role in cognition and, when dysregulated, promotes neuropathological conditions. To understand the impact of Cdk5 dysregulation in neural disease, it is essential to elucidate the basic physiological functions of Cdk5 in the neuron. In this application, we will test the hypothesis that Cdk5 plays a key role in synaptic function and cognition, and that dysregulation of Cdk5 is detrimental to the nervous system. Using a multidisciplinary approach involving techniques of biochemistry, electrophysiology, and behavior, as well as taking advantage of a novel knock-in p35 mutant mouse, we will dissect the physiological and pathological roles of Cdk5 in synaptic plasticity and neurodegeneration, respectively. Completion of this project will lead to a greater understand the pathogenesis of Alzheimer's-like neurodegenerative diseases, and will elucidate promising targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Current treatment approaches for Alzheimer's disease have led to failed drug trials, discouraged researchers, and an increasing sense of desperation in a vulnerable aging population. In combating neurodegenerative disease, it is imperative that we explore in detail the molecular mechanisms involved in the aberrant physiology and neuronal dysfunction that results in defects in synaptic plasticity and learning and memory. In the current application, by greatly expanding our understanding of the role of Cdk5/p25 signaling in both normal synaptic function and neuropathology, we hope to discern novel targets for drug development in Alzheimer's disease and other neurodegenerative disorders.