Alzheimer's disease is the most common form of dementia. It affects about 5 million Americans, and there is no known cure. Cdh1 is a protein that activates the anaphase promoting complex (APC) and binds specific proteins so that they can be marked for degradation. Cdh1 is well known for its role in advancing the cell cycle through the end of mitosis and maintaining cells in G1 interphase. Interestingly, Cdh1 has been discovered in post-mitotic neurons, cells that no longer undergo the cell cycle, suggesting a novel role for Cdh1 in neurons. Recent work indicates that Cdh1 is involved in synaptic plasticity and maintaining neurons in their post-mitotic state, thus preventing aberrant cell cycle reentry that leads to neuronal death. On a large scale, this neuronal death may result in Alzheimer's disease. My objective is to use a vertebrate system to examine the involvement of Cdh1 in synaptic plasticity and memory, as well as identify the molecular mechanism involved in its regulation.
Aim I - Using electrophysiology, I will examine the hypothesis that synaptic plasticity is altered in conditional Cdh1 knockout mice.
Aim II - With behavioral experiments, I will test the hypothesis that Cdh1 knockout mice display impaired memory phenotypes and their neurons show signs of aberrant cell cycle reentry.
Aim III - Using biochemical and molecular techniques, I will test the hypothesis that Cdk5 phosphorylates and regulates Cdh1 function in neurons. Together, these experiments will attempt to provide in vivo evidence for the involvement of Cdh1 in neuronal plasticity on several levels. This study could provide evidence that Cdh1 activity helps prevent the onset of Alzheimer's disease by maintaining neurons in a post-mitotic state by preventing cell cycle reentry which would lead to neuronal death. Understanding both the regulatory mechanism of Cdh1 and its involvement in plasticity and memory will allow new therapeutic targets to prevent the onset of Alzheimer's disease
|Pick, Joseph E; Wang, Li; Mayfield, Joshua E et al. (2013) Neuronal expression of the ubiquitin E3 ligase APC/C-Cdh1 during development is required for long-term potentiation, behavioral flexibility, and extinction. Neurobiol Learn Mem 100:25-31|
|Pick, Joseph E; Malumbres, Marcos; Klann, Eric (2012) The E3 ligase APC/C-Cdh1 is required for associative fear memory and long-term potentiation in the amygdala of adult mice. Learn Mem 20:11-20|