Anti-phosphorylation Drugs May Treat Alzheimer's

Researchers seeking to develop drugs to prevent or treat Alzheimer's disease have identified three molecules that seem to prevent the phosphorylation of tau proteins. This phosphorylation leads to the development of cytotoxic inclusions that cause the death of critical brain cells.

Tau is a protein associated with microtubules in neurons. In Alzheimer's disease, various other neurodegenerative conditions, and inflammation, tau becomes highly phosphorylated, dissociates from microtubules, and forms neurofibrillary tangles, causing cell death.

Investigators at the University of California, Santa Barbara (USA), screened more than 58,000 compounds in the search for any that might protect tau from phosphorylation. In the July 25, 2005, issue of Chemistry and Biology, they reported finding three molecules that inhibited the activity of the CDK5 (cyclin-dependent kinase 5) enzyme that attaches the phosphate moieties to the tau protein.

One compound was shown to be competitive with ATP (adenosine triphosphate, the source of phosphate groups) and had a high affinity for the Cdk5 ATP binding pocket. The second compound also competed with ATP, was noncompetitive with tau, and (uniquely among this class of inhibitors) displaced adjacent amino acid residues to make room for the nitrophenyl group. A third compound did not compete with ATP, but did compete with tau at low concentrations of tau.

Research will be continuing in order to determine if any of these compounds can be developed into drugs. "This is the first demonstration that we can find small molecules that can more specifically affect the phosphorylation of tau by CDK5,” said senior author Dr. Ken Kosik, professor of neurosciences at the University of California, Santa Barbara. "There is a lot to do here, lab testing, testing in animals, and so forth. But we have made an important step forward toward developing treatments for this disease.”




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