Alzheimer's disease (AD) is a metabolically complex, neurodegenerative disorder that we hypothesize results from abnormal protein processing and aggregation. In particular, alterations in the proteolytic processing of the amyloid precursor protein (APP) are thought to lead to the generation of the beta amyloid peptide, which is one key element in the proteinaceous deposits of cell plaques. Our overall goal is to investigate candidate proteases that might affect the cellular processing of APP and, thus, represent, a risk factor for AD and a potential target for therapeutic intervention. Recent experimental evidence suggests a unique neutral cysteine protease, called bleomycin hydrolase, may have a role in AD. This enzyme has two polymorphic forms, one of which is associated with an increased risk for sporadic AD. We propose to use both in vitro and in vivo models to evaluate the biochemical functions of both polymorphic forms of this protease.
Our Specific Aims are: (1) Investigate the physical interactions between the isoleucine and valine polymorphic forms of human bleomycin hydrolase (hBlmh) and AD-linked proteins, including APP, alpha`, anti-chymotrypsin, presenilin 2; (2) Assess the biochemical consequences of interactions between hBlmh polymorphic forms and putative AD proteins; (3) Determine whether or not hBlmh colocalizes with putative AD proteins within cells and (4) Characterize the neuritic plaque formation and cognitive functions of transgenic mice lacking Blmh that have been bred with mice expressing human amyloid precursor protein with familial AD gene mutants. These studies should provide new mechanistic information concerning the pathogenesis of AD as well as reagents for future therapeutic studies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005133-19
Application #
6589718
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2002-05-15
Project End
2003-03-31
Budget Start
Budget End
Support Year
19
Fiscal Year
2002
Total Cost
$158,272
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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