Steady-state levels of the amyloid beta-protein (ABeta), which accumulates abnormally in Alzheimer's disease (AD), reflect the balance between the key processes of production, via the beta- and gamma- secretases, and proteolytic degradation, by one or more proteases. While therapies based on pharmacological blockade of the secretases have been extensively studied, very little work has examined the complimentary approach of activating or disinhibiting ABeta degrading proteases. Recent evidence shows that molecules that bind tightly to ABeta in the periphery (e.g., antibodies, gelsolin) can decrease levels of ABeta in the brain in a reaction akin to dialysis, indicating that central and peripheral pools of ABeta exist in rapid equilibrium. By extension, we hypothesize that enhancing degradation of ABeta in the periphery will also lower brain ABeta levels, an idea we call the """"""""peripheral degradation hypothesis."""""""" To test this new hypothesis, and to identify novel drug targets and small molecule pharmacophores acting on peripheral ABeta degradation, we propose the following Aims. First, to directly test the peripheral degradation hypothesis, ABeta-degrading proteases will be overexpressed exclusively in the periphery of APP transgenic mice by using adenovirus with liver-specific promoters. Second, to identify the principal ABeta-degrading proteases in the periphery in vivo, the rate of clearance of intravenously administered AB3eta will be compared in wildtype mice and in mice lacking specific ABeta-degrading proteases. In addition, the major ABeta-degrading proteases in human serum will be identified using protease-specific inhibitors. Third, in collaboration with the Laboratory for Drug Discovery in Neurodegeneration, a high throughput ABeta-degradation assay will be performed on approximately 60,000 small molecule pharmacophores using human serum or recombinant proteases as the source of ABeta degrading activity. Collectively, the studies outlined in this proposal will evaluate--and potentially enhance--the potential of peripheral ABeta-degrading proteases as novel therapeutic targets in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AG025070-02
Application #
7013584
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Snyder, Stephen D
Project Start
2005-02-15
Project End
2007-10-05
Budget Start
2006-03-01
Budget End
2007-10-05
Support Year
2
Fiscal Year
2006
Total Cost
$166,352
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Leissring, Malcolm A; Malito, Enrico; Hedouin, Sabrine et al. (2010) Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS One 5:e10504
Neant-Fery, Marie; Garcia-Ordonez, Ruben D; Logan, Todd P et al. (2008) Molecular basis for the thiol sensitivity of insulin-degrading enzyme. Proc Natl Acad Sci U S A 105:9582-7