This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It has been postulated that the development of amyloid plaques in Alzheimers disease (AD) may result from an imbalance between the generation and clearance of the amyloid-beta peptide (A ). Although familial AD appears to be caused by A overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of A . Furthermore, astrocytes have recently been implicated as a potential cellular mediator of A degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs, proteases known to be expressed and secreted by astrocytes) could play a role in extracellular A' degradation. We found that astrocytes surrounding amyloid plaques demonstrated enhanced expression of MMP-2 and MMP-9 in aged APP/PS1 mice. Moreover, conditioned medium from cultured astrocytes (ACM) degraded A , lowering levels and producing several fragments after incubation with synthetic A 1-40 and A 1-42. This activity was attenuated with specific inhibitors of MMP-2 and 9, as well as in ACM derived from mmp-2 or -9 knockout mice. In vivo, significant increases in the steady-state levels of A were found in the brains of mmp-2 and -9 knockout mice compared to wild-type controls. Furthermore, pharmacological inhibition of the MMPs with GM6001 increased brain interstitial fluid (ISF) A levels and elimination half-life in APPsw mice. These results suggest that MMP-2 and -9 may contribute to extracellular brain A clearance by promoting A catabolism.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR000954-30
Application #
7597704
Study Section
Special Emphasis Panel (ZRG1-BPC-H (40))
Project Start
2007-02-01
Project End
2008-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
30
Fiscal Year
2007
Total Cost
$4,632
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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