Researchers discovered three molecules that appear to inhibit a key perpetrator of Alzheimer's disease.
Each of the three molecules protects the protein called "tau," which becomes hopelessly tangled in the brains of patients with Alzheimer's.

Alzheimer's involves a complicated, interwoven series of regulatory steps of genes and proteins "talking" to each other, Kosik co-director of the Neuroscience Research Institute at the University of California, Santa Barbara, explained. "When the conversation goes awry the disease process begins. And it is not just one gene or one protein causing the damage."

The complexity of Alzheimer's means that several different medications will likely be needed to control it, said Kosik. The same is true for many other diseases –– from AIDS to cancer. "It is likely that we will need to strategically target different aspects of the disease and put them together."

Kosik and his team chose to focus on the neurofibrillary tangles of neurons in the brain that, along with senile plaques, characterize Alzheimer's disease. The tangles are made of "tau," a protein that is also present normally in the brain.

"Tau goes wrong and becomes pathological when it becomes intensely phosphorylated," said Kosik. "This means that many phosphate groups attach to tau--modify it--and cause it to become dysfunctional."

The culprit is an enzyme, called CDK5, that attaches the phosphate to the tau protein, facilitating the disease process. The researchers set out to find a way to inhibit this enzyme, to keep it from putting any phosphate on tau.

In the laboratory, they purified the enzyme and purified tau protein, and watched tau get phosphorylated by the enzyme. They then performed a library search of small molecules ( 58,000 of them ) in an attempt to find those that would prevent phosphorylation. Small molecules are preferred because they are more easily used as a drug since they can get through the body and into cells. It is also important to find molecules that will cross the blood brain barrier.

They then set up a test of nearly 400 small molecules that fit their criteria. The test results showed three small molecules that can inhibit the enzyme. These are candidates for development as drugs.

Kosik explained that proteins are strings of amino acids folded into small globs. All proteins that happen to be an enzyme involved in phosphorylation have one thing in common. They have a pocket that is almost always in the same place and this is where the phosphate attaches to the enzyme, in this case CDK5. To get a molecule that specifically prevents the enzyme from binding at the pocket is difficult.

Of the three compounds that the research group found, the scientists were able to locate where they bind. They found that one binds in the pocket, another binds at the edge of the pocket, and a third appears to bind completely outside the pocket. The scientists are most interested in the second and third compounds.

"This is the first demonstration that we can find small molecules that can more specifically affect the phosphorylation of tau by CDK5," said Kosik.

Source: University of California - Santa Barbara, 2005


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