For release: Monday, September 26, 2005
While several treatments are currently available for Alzheimer's disease (AD), none of them can slow or halt the course of this devastating disorder. In a new study, researchers have now identified three compounds that inhibit an enzyme believed to be involved in the process that leads to AD. This discovery may lead to new treatments that can stop the disease process in its tracks.
"Because of recent advances in understanding Alzheimer's disease, we are now moving strongly toward devising therapies that will treat the disease," says Kenneth Kosik, M.D., of the Neuroscience Research Institute at the University of California, Santa Barbara (UCSB), who led the new study. Dr. Kosik and his colleagues tested thousands of compounds to learn if any of them could interfere with an enzyme called Cdk5. This enzyme helps to form bundles of twisted filaments found within neurons, called neurofibrillary tangles, which are a hallmark of AD. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the July 22, 2005, issue of Chemistry & Biology.*
Neurofibrillary tangles are composed largely of a protein called tau. In healthy neurons, tau is a component of microtubules, which form part of the cell's structural support and deliver substances throughout the nerve cell. However, in AD, tau gets attached to many molecules called phosphate groups. These phosphate groups change the protein's structure and function and cause it to form tangles. Previous studies have shown that Cdk5 helps the phosphate groups attach to tau. Therefore, researchers hypothesize that inhibiting Cdk5 might stop neurofibrillary tangles from forming and prevent some of the neuron loss in AD.
The investigators tested drug-like molecules that are small enough to enter the brain and penetrate neurons. With additional development, these molecules could serve as the basis for future drugs to treat neurodegenerative disorders such as AD, Niemann-Pick disease, and Parkinson’s diseases. Using a new "high-throughput" screening test, the researchers rapidly tested 58,000 molecules from a chemical library to see if any of them would prevent Cdk5 from adding phosphate groups to tau – a process called phosphorylation. They identified three compounds that worked. One of the compounds was similar to other, previously identified inhibitor compounds. However, the other two compounds worked in previously undescribed ways.
The researchers are particularly interested in one of the compounds because it binds to Cdk5 and prevents tau phosphorylation in a manner that is unlikely to interfere with other activities of the enzyme. Since Cdk5 and similar enzymes have many different roles in the body, stopping their activity completely could cause many side effects. Therefore, researchers want to find a drug that can selectively inhibit Cdk5's ability to modify tau without interfering with its other functions.
While none of the three compounds identified in this study works well enough to be a strong drug candidate for AD, learning how these compounds work could help biochemists modify them in ways that would increase their effectiveness, Dr. Kosik says. They also might be able to use this knowledge to identify or design new, more effective compounds.
In addition to AD, Cdk5 has been linked to development of Parkinson's disease, amyotrophic lateral sclerosis, and Niemann-Pick disease type C. While it is not yet clear exactly how the enzyme contributes to these diseases, a Cdk5-blocking drug developed to treat AD might also be useful for treating them, the researchers say.
This drug screening project is unique in that it was conducted by a group of university researchers rather than at a pharmaceutical company. Early-stage drug discovery can sometimes proceed more rapidly in academic settings because university researchers don't share the same market-driven concerns as companies, Dr. Kosik comments. He also credits the success of this project to "extraordinary collaborators" from Harvard Medical School in Boston, the Massachusetts Institute of Technology in Cambridge, and Italy. The project began while Dr. Kosik worked at Harvard.
The researchers are continuing their drug screening efforts and they have now tested about 100,000 compounds, Dr. Kosik says. They also are exploring ways to modify the Cdk5-blocking compounds they've identified and they are looking to biochemistry and to natural substances to find new compounds to screen. He hopes they might eventually identify compounds that can specifically inhibit the transfer of phosphate groups to tau, instead of interfering with Cdk5. Such compounds would allow a much more precise way of treating AD, he adds.
The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Ahn JS, Radhakrishnan ML, Mapelli M, Choi S, Tidor B, Cuny GD, Musacchio A, Yrh L-A, Kosik KS. "Defining Cdk5 Ligand Chemical Space with Small Molecule Inhibitors of Tau Phosphorylation." Chemistry & Biology, July 2005, Vol. 12, No. 7, pp. 811-823.
-By Natalie Frazin
Last Modified January 31, 2007