With the recent demonstration by this laboratory and others (i) that the amyloid beta protein precursor (betaAPP) is constitutively processed by betaAPP secretase to produce identifiable derivatives, (ii) that the endosomal-lysosomal system processes identifiable carboxyl-terminal betaAPP derivatives likely to be important intermediates in the pathway that produces amyloid, and (iii) that 4 kD amyloid beta protein (Abeta) is normally produced and released by cultured cells, it is now realistic to undertake the identification of the key proteases that determine the amount of Abeta produced. Here, we propose experimentation focused on the identification of betaAPP secretase that will explore the feasibility of rapidly identifying these proteases using antisense cDNA expression libraries. We plan to focus on betaAPP secretase in these experiments because it is likely to be difficult to isolate this unusual and critically important enzyme conventionally using in vitro assays based on sequence specificity and because the knockout of betaAPP secretase with antisense cDNAs will almost certainly increase the level of surface betaAPP to a degree that can be detected by fluorescence activated cell sorting.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG008012-11S2
Application #
6295463
Study Section
Project Start
1999-06-01
Project End
2000-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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