Molecular targetsof Synaptic Dysfunction in AD

Michael Ehlers, MD, PhD
Duke University (Durham, NC)
Year Awarded:
2004
Grant Duration:
April 1, 2004 to March 31, 2006
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2004004
Award Type:
Standard
Award Region:
US Southeastern

Molecular targetsof Synaptic Dysfunction in AD

Details


A significant amount of early memory deficit in Alzheimer's disease (AD) is caused by abnormal communication between nerve cells in the hippocampus, a brain region dedicated to memory formation. Such communication occurs at excitatory synapses, specialized cell-cell contact sites where the neurotransmitter glutamate is released and detected. A prominent form of AD-associated synapse dysfunction is the impairment of synaptic plasticity by beta-amyloid (Aß), the protein fragment that accumulates in the brains of Alzheimer's patients. A newly recognized mechanism for changing synaptic strength is the removal of neurotransmitter receptors that detect the neurotransmitter glutamate by a process called endocytosis. Dr. Ehlers has found that Aß peptides cause a selective activation of endocytosis molecules with a simultaneous loss of glutamate receptors at hippocampal synapses. Using his preliminary data, Dr. Ehlers is working to define the underlying cellular mechanism of the Aß-dependent disturbance of endocytosis and to identify molecular signals that restore normal synapse function in the amyloid-exposed brain.

Publications

Kennedy, M. J. and Ehlers, M.D. (2006) Organelles and trafficking machinery for postsynaptic plasticity. Annual Rev. Neurosci. 29:325-362.  

Perez-Otano, I., Lujan, R., Tavalin, S.J., Plomann, M., Modregger, J., Liu, X.B.,Jones, E.G., Heinemann, S.F., Lo, D.C., and Ehlers, M.D. (2006) Endocytosis and synaptic removal of NR3A-containing NMDA receptors by SIN1/syndapin1. Nature Neuroscience. 9(5):611-21.  

Terry-Lorenzo, R.T., Roadcap, D.W., Otsuka, T., Blanpied, T.A., Zamorano, P.L., Garner, C.C., Shenolikar, S., and Ehlers, M.D. (2005) Neurabin/protein phosphatase-1 complex regulates dendritic spine morphogenesis and maturation. Molecular Biology of the Cell. 16(5):2349-2362.  

Perez-Otano, I. and Ehlers, M.D. (2005) Homeostatic plasticity and NMDA receptor trafficking. Trends in Neurosciences. 28(5):229-38.  

Yi, J.J. and Ehlers, M.D. (2005) Ubiquitin and protein turnover in synapse function. Neuron. 47(5):629-632.  

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