Although our understanding of the pathogenesis of Alzheimer's disease (AD) has advanced enormously over the past decade, the link between the pathology of the disease and its devastating cognitive symptoms remains unclear. An exciting possibility for this connection recently came to light in the discovery of a direct interaction between the Abeta peptide found in amyloid lesions of AD and a neurotransmitter receptor that modulates synaptic function in parts of the brain most afflicted by the disease. Not only does the alpha7 acetylcholine receptor bind strongly and specifically to Abeta, but in so doing, its response to stimulation by acetylcholine is significantly altered. This interaction could substantially affect cholinergic transmission in areas of the brain rich in both Abeta and alpha7, including the cortex and the hippocampus. However, most of the research to characterize this interaction to date has focused the peptide's acute effects in preparations often quite unrelated to the adult brain. Our proposed experiments will extend these earlier findings in several important ways. First, we will address the functional consequences of Abeta exposure by examining alpha7-mediated neurotransmitter release and calcium homeostasis in hippocampal neurons. Second, we will use an acute slice preparation from postnatal animals that retains much of the normal neuronal connectivity found in vivo. Third, we will explore how prolonged exposure to Abeta influences alpha7-mediated synaptic function, and how this compares to the peptide's acute effects. Fourth, we will examine whether binding to alpha7 later promotes aggregation of Aa and the formation of amyloid plaques. Finally, we will determine the binding site for Abeta on the alpha7 receptor. Thus our proposed research will assess the functional and pathological changes caused by the binding of Abeta to alpha7, and determine the site on the receptor where this interaction takes place with the long term prospect of pharmaceutical intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG026144-02
Application #
6952289
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Snyder, Stephen D
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$124,470
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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