The overall goal of the studies proposed in this revised exploratory R21 application is to further explore the anti-amyloidogenic role of D-pinitol, a traditional insulin sensitizer herbal agent, in Tg2576 mice that model Alzheimer's disease (AD) amyloid neuropathology. The studies are supported by the feasibility evidence suggesting that a mechanism by which D-pinitol may prevent AD neuropathology in the brain of Tg2576 mice is through the inhibition of beta-amyloid (A(B) peptide generation. This may occur through a mechanism that prevents the generation of the gamma-CTF from amyloid precursor protein (APR), which is an index of gamma-secretase activity, without influencing normal Notch processing. Most interestingly, we also found that D-pinitol may prevent AB peptide generation and gamma-secretase at concentrations as low as 10 uM without evidence of cellular toxicity. Thus, it is possible that D-pinitol, in addition to its potential anti-amylolidogenic role as insulin-sensitizing agent, may also prevent AB peptide generation through direct modulation of a mechanism involved in gamma-secretase activation. Based on this new exciting evidence, the studies proposed in this revised application were designed to test the hypothesis that D-pinitol may alleviate AD amyloidosis in Tg2576 mice through mechanisms 1) dependent on the reversal of insulin-resistance and/or 2) through direct modulation of mechanisms ultimately resulting in decreased generation (or increased degradation) of amyloidogenic AB peptides. In view of the evidence that the amyloid hypothesis of AD maintains that the accumulation of the AB in the brain is a critical event in disease pathogenesis, the proposed studies will provide a unique opportunity for evaluating a novel therapeutic role of D-pinitol in AD.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AT002602-01A1
Application #
6988826
Study Section
Special Emphasis Panel (ZAT1-DB (18))
Program Officer
Pearson, Nancy
Project Start
2005-09-01
Project End
2007-07-31
Budget Start
2005-09-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$211,875
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029