Understanding the body's natural clearance of accumulated protein deposits

Enrico Malito, PhD
University of Chicago (Chicago, IL)
Year Awarded:
2007
Grant Duration:
April 1, 2007 to March 31, 2009
Disease:
Alzheimer's
Award Amount:
$100,000
Grant Reference ID:
A2007619
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern

Insulin Degrading Enzyme and Control of Amyloid B Levels

Mentors

Wei-Jen Tang, Ph.D.
University of Chicago

Summary

We propose to further investigate the molecular mechanism by which Insulin Degrading Enzyme (IDE) exerts its function, with the final aim of finding a hyperactive form of IDE able to more effectively degrade the protein responsible for the onset of Alzheimer's disease. These studies will provide valuable insights into the design of IDE-based therapeutics against Alzheimer's disease.

Details


Accumulation in the brain of a specific protein in the form of insoluble plaques is a critical event in Alzheimer's disease pathology. The imbalance between production of this protein and its degradation is the critical event responsible for its accumulation. Investigating the defects of enzymes that degrade this protein is an essential effort for a better understanding and for the treatment of Alzheimer's disease. Insulin degrading enzyme (IDE) is among the enzymes responsible for the degradation of the peptide that then accumulates in the brain in an insoluble form, and IDE deficiency is correlated with a significant net increase in accumulation of insoluble plaques in the brain. Consequently, IDE represents a new target for the development of drugs for the treatment of Alzheimer's disease. Our structural studies of IDE allowed us to understand the basic features of this important enzyme. Starting from these observations we can now modify IDE in order to obtain a decrease of accumulated insoluble plaques. We propose to further investigate the molecular mechanism by which IDE exerts its function, with the final aim of finding a hyperactive form of IDE able to more effectively degrade the protein responsible for the onset of Alzheimer's disease. These studies will provide valuable insights into the design of IDE-based therapeutics against Alzheimer's disease.

Publications

Im, H., Manolopoulou, M., Malito, E., Shen, Y., Zhao, J., Neant-Fery, M., Sun, C.Y., Meredith, S.C., Sisodia, S.S., Leissring, M., and Tang, W.J. (2007) Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J. Biol. Chem. 282(35):25453-25463.