Alpha7 Nicotinic Receptors and MAP Kinase in AD Models

David Sweatt, PhD
Baylor College of Medicine (Houston, TX)
Year Awarded:
2002
Grant Duration:
April 1, 2002 to March 31, 2004
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2002001
Award Type:
Standard
Award Region:
US Southern

Alpha7 Nicotinic Receptors and MAP Kinase in AD Models

Details


Early stage Alzheimer's disease is generally observed as hippocampal dysfunction with the inability of the brain to consolidate short-term into long-term memories. These memory deficits are typically present before any generalized dementia or overall cognitive decline is observed. Dr. Sweatt hypothesizes that for the early stages of AD, which are characterized by subtle deficits in memory consolidation; there will be abnormalities in the normal biochemical machinery that underlies memory. He suggests that the MAP kinase signaling cascade plays a critical role in learning and memory. He is examining the transgenic mouse model of AD for MAP kinase signaling defects. He will also examine how the amyloid beta peptide is linked to the MAP kinase cascade. Preliminary results suggest that a receptor for amyloid beta peptide on the cell surface of neurons is the alpha7 nicotinic acetylcholine receptor. Dr. Sweatt will use genetic approaches to examine whether deletion of the alpha7 receptor gene leads to amelioration of memory deficits exhibited in transgenic mice with AD and decreases in biochemical markers. The identification of the alpha 7 receptor involvement in AD allows for the future study of agents that block the receptor as potential therapeutics for AD.

Publications

Dineley, K., Xia, X., Bui, D., Sweatt, J.D., and Zheng, H. (2002) Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein In transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor protein. J. Biol Chem. 277:22768-80.  

Dineley, K.T., Bell, K.A., Bui, D., and Sweatt, J.D. (2002) Beta-amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol Chem. 277(28):25056-25061.  

Weeber, E.J., Beffert, U., Jones, C., Christian, J.M., Forster, E., Sweatt, J.D., and Herz, J. (2002) Reelin and ApoE receptors cooperate to enhance hippocampal synapitc plasticity and learning. J. Biol Chem. 277(42):39944-39952.  

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