2009-2010 ARDRAF Final Project ReportMechanisms for Cdk5-mediated synaptic depression
Mechanisms for Cdk5-mediated synaptic depression
J. Julius Zhu, PhD, and Lei Zhang, PhD
University of Virginia
This project investigates the central hypothesis that Cdk5 is a novel rapid homeostatic transmission regulator and aberrant Cdk5 signaling causes the synaptic depression associated with Alzheimer’s disease. Preliminary evidence indicated that synaptic activity regulates Cdk5 signaling, which in turns induces a beta-amyloid-independent synaptic depression. The activity-stimulated Cdk5 signaling rapidly depresses transmission independent of transcription and translation, and it depresses NMDA responses prior to AMPA responses, distinguishing itself from beta amyloid (Aβ) and other homeostatic transmission regulators. This suggests that Cdk5 imposes a new type of fast and fine homeostatic regulation on synaptic transmission and dysfunction of Cdk5 signaling is responsible for the early pathogenesis of Alzheimer’s disease. Although a number of molecules, including Aβ and a specific Cdk5 activator p25, have been implicated in Alzheimer’s disease, it remains unclear which molecule(s) are responsible for the early synaptic pathogenesis. This study has identified p25 as the first molecule responsible for the early pathogenesis of Alzheimer’s disease. The results explain the lack of correlation between Aβ deposition and cognitive impairment observed in AD patients and may also account for the failed clinical trials blocking Aβ, which should complementarily stimulate more homeostatic Cdk5 signaling and synaptic depression. The findings suggest additional molecular targets and provide the scientific foundation for developing new detection and treatment strategies for Alzheimer’s patients.
(Dr. Zhu may be contacted at 434/243-9246; Dr. Zhang may be contacted at 434/243-9562)
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