Age-related Disorders - Malcolm A. Leissring

High-Throughput Screening

Dr. Leissring's lab uses robotics for high-throughput compound screening.

Once novel drug targets have been identified and validated in vivo and appropriate assays have been developed, it becomes possible to screen large collections of compounds in search of drug-like compounds that affect the target in appropriate ways.

The laboratory of Malcolm A. Leissring, Ph.D., uses these well-characterized animal models to test novel therapeutic approaches to treating and preventing neurodegenerative diseases. For example, Dr. Leissring's group was the first to show that neuronal overexpression of proteases that degrade the amyloid-beta (Aβ) protein can attenuate or even completely prevent Alzheimer-type pathology in amyloid precursor protein (APP) transgenic mice (see figure).

The discovery that proteolytic degradation of Aβ potently regulates amyloidogenesis has numerous implications for the pathogenesis and prevention of Alzheimer's disease. Dr. Leissring's laboratory is currently pursuing a number of very promising projects derived from this seminal discovery.

This is a summary of these projects:

As an example of the outcomes of these efforts, the lab recently described the discovery of the first drug-like compounds capable of activating the proteolytic activity of IDE in vitro. For more information, see:

• Cabrol C, et al. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS One. 2009;4:e5274.