The mechanisms that contribute to death of neurons in Alzheimer's disease remain to be defined. This is a particularly important process because loss of neurons and synapses likely play a critical role in cognitive impairment and indeed, may even precede clinical manifestations of the disease. Recent studies consistently showed that many mutations associated with neurodegenerative disease result in a pro-apoptotic phenotype in culture and, furthermore, many of the neurodegeneration-associated gene products are generally believed to be the """"""""executioners"""""""" of the cell death program. We have recently found that the mutant androgen receptor associated with Kennedy's syndrome (spinobulbar muscular atrophy) is a caspase substrate, and, more importantly, that mutation of the caspase cleavage site blocks the pro-apoptotic effects of the mutant gene. This result argues that caspase cleavage in this case is an important event in the induction of cell death. Recently, it has been shown that three important Alzheimer's disease associated-genes, amyloid precursor protein, presenilin-1, and presenilin-2, are all caspase substrates. Therefore, the working hypothesis that guides this project is that caspase cleavage of these three gene products is required for cell death promoting properties associated with the familial Alzheimer's disease (FAD) mutations. In this application, we propose to explore the relationship between caspase cleavage of these three proteins and cell death. The results of these studies should help determine whether caspase cleavage represents an important signaling event in cell death in culture included by these mutant proteins. Furthermore, an understanding of this relationship will affect the development of new therapeutic strategies to treat Alzheimer disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005131-17
Application #
6398174
Study Section
Project Start
2000-04-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
17
Fiscal Year
2000
Total Cost
$9,240
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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