The neuronal production of amyloid beta (beta) from the amyloid precursor protein (APP) appears to be a necessary and invarieant step in the progression of Alzheimer's disease (AD). Three genes have been linked to early-onset AD. These genes are presenilin 1 (PS1), presenilin 2 (PS2), and APP itself. Mutations in each of these genes lead to the elevated proteolytic processing of APP into Abeta species that aggregate more readily and form amyloid plaques. The fact that three separate genes implicate Abeta as the causative agent of Alzheimer's disease makes this an important target for theraputic intervention. One way to create therapies for AD is to block the proteases that generate Abeta. These proteases have not been unidentified but the activities that create Abeta are termed beta and gamma secretase. The role of gamma secretase is especially important in the progression of AD since this activity can produce more or less aggregating forms of Abeta. It is the aim of this proposed study to characterize the role of PS1 in gamma secretase activity, identifying the subcellular localization of gamma secretase activity, and lastly to identity the gamma secretases. This will be accomplished through biochemical manipulation of cell extracts and monitoring gamma secretase activity in an in vitro assay. The identification of the protease(s) involved in producing abeta at the gamma secretase site will drastically further knowledge of the molecular mechanisms underlying AD and improve chances of creating theraputic inhibitors that slow or stop the progression of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
3F32AG005887-03S1
Application #
6845211
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Snyder, Stephen D
Project Start
2002-01-22
Project End
2005-01-21
Budget Start
2004-02-17
Budget End
2005-01-21
Support Year
3
Fiscal Year
2004
Total Cost
$42,648
Indirect Cost
Name
University of Melbourne
Department
Type
DUNS #
753575117
City
Melbourne
State
Country
Australia
Zip Code
3010