Alzheimer's disease (AD) is a metabolically complex, neurodegenerative disorder that we hypothesize results from abnormal protein processing aggregation. In particular, alterations in the proteolytic processing of the amyloid precursor protein (APP) are thought to lead to the generation of beta amyloid peptides (Abeta), which are key elements in the proteinaceous deposits of cell plaques. Our overall goal is to investigate candidate proteases that might affect the cellular intervention. Recent experimental evidence suggests a unique neutral cysteine protease, bleomycin hydrolase (BH), may have a role in AD. This enzyme has tow polymorphic forms, one of which has been genetically associated with an increased risk for sporadic AD. Biochemical studies indicate ectopic expression of bleomycin hydrolase in cultured cells enhances Abeta secretion. Cysteine73, which is critical for cysteine protease activity, also is required for enhanced Abeta deposition in cultured cells. We now propose to use both in vitro and in vivo models to evaluate further the biochemical functions of this unique protease with a particular emphasis on neuronal cells.
Our Specific Aims are: (1 Investigate the physical interactions between human bleomycin hydrolase (hBH) and AD-linked proteins, including APP, FE65, mDAB, X11, nicastrin, BACE-1, presenilin 1 and presenilin 2; (2) Assess the biochemical consequences of interactions between hBH and putative AD proteins; (3) Determine whether or not hBH is expressed and colocalized with putative partner proteins within cells and (4) Characterize the histopathology and cognitive functions of transgenic mice lacking BH 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
Research Project (R01)
Project #
5R01AG018557-04
Application #
6785337
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-09-01
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$274,554
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Montoya, S E; Thiels, E; Card, J P et al. (2007) Astrogliosis and behavioral changes in mice lacking the neutral cysteine protease bleomycin hydrolase. Neuroscience 146:890-900
Vasudevan, Sanjeev A; Skoko, John; Wang, Kuan et al. (2005) MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun 330:511-8