Grant: Operating Grant

Alzheimer's disease (AD) is the most common neurodegenerative disorder, with over 18 million people worldwide afflicted by this disease. Cognitive symptoms in AD correlate with loss of synapses that results from impaired synaptogenesis. Cyclin-dependent kinase 5 (Cdk5), which is abundant in the synapse and modulates synaptogenesis, is aberrantly upregulated in AD. The notion is that Cdk5 deregulation results in synaptic and cognitive impairment in AD. Cdk5 activation requires interaction with p35 or p39, but recently, we made the discovery that phospholipase D2 (PLD2) binds and activates Cdk5, and Cdk5-PLD2 interaction promotes synaptogenesis. Interestingly, we observed increased Cdk5-PLD2 interaction in the 5XFAD AD mouse model, which exhibits increased Cdk5 activity, neuronal loss, and synaptic and cognitive failures. Thus, although Cdk5 activity is required for normal synapse dynamics, overactivation is detrimental and may contribute to neurodegeneration. Our HYPOTHESIS is that a subset of Cdk5-mediated synaptogenesis is modulated by Cdk5-PLD2 through specific targets. Two Cdk5 substrates that promote synaptogenesis are the calcium-calmodulin-dependent serine protein kinase (CASK) and PLD2. We also found that beta-adducin, a protein kinase C delta substrate, is a Cdk5 downstream target. These led us to a model in which Cdk5-PLD2 targets proteins that promote synaptogenesis. Our overall OBJECTIVE is to understand how Cdk5-PLD2 mediates synaptogenesis. Our SPECIFIC AIMS are to examine whether: (a) CASK and PLD2 are preferred Cdk5-PLD2 substrates, (b) Cdk5-PLD2 activity mediates changes in synaptic currents, and (c) Cdk5-PLD2 modulates synaptogenesis through CASK, PLD2 and the PKC delta-beta-adducin pathway, and investigate whether Cdk5-PLD2 contributes to neuronal loss in 5XFAD mice. Understanding the mechanism by which Cdk5-PLD2 regulates synaptogenesis could provide new clues in the design of new therapies for impaired cognitive symptoms in AD.