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Alzheimer’s, Stroke Researcher Receives 10-Year MERIT Award

Tuesday, November 09, 2004

            A researcher exploring ways to keep our brains healthy against the ravages of stroke and Alzheimer’s has been awarded a rare 10-year MERIT award from the National Institute on Aging.

            Berislav Zlokovic, M.D., Ph.D., received the award, worth approximately $5 million in funding during the next 10 years, to further his research that is opening up new ways for scientists to treat or prevent Alzheimer’s disease. Zlokovic didn’t apply for the award; rather, his peers at NIH selected him based on the consistent high quality of his work over several years.

            Zlokovic specializes in studying the crucial role of blood vessels in diseases like Alzheimer’s, an approach that goes back to the days when German physician Alois Alzheimer first diagnosed the disease nearly 100 years ago. Zlokovic says Alzheimer noted changes in both the brain’s cells and the arteries and veins that supply and drain blood to and from the brain. But 50 years later, doctors separated the two concepts and then focused mainly on how brain cells die, even though it’s widely known that other forms of dementia are caused mainly by problems with the blood vessels.

            Zlokovic has brought the blood vessel component of Alzheimer’s disease back into prominence. He has shown that blood circulation plays a key role in ridding the brain of toxic amyloid beta that speckles the brains of Alzheimer’s patients. His team has identified much of the molecular machinery that allows amyloid beta to sidestep the body’s safeguards and enter the brain, and in mice he has found ways to stop the protein from getting into the brain. And he has shown how the same molecules can affect blood vessels, causing blood flow to plummet.

           In August his team published a paper in Neuron, a top neuroscience journal, where the scientists demonstrated some of the complexity of the process. The team found that several forms of amyloid beta compete with each other for removal from the brain: The removal system is kept busy shuttling relatively harmless forms of amyloid beta across the blood-brain barrier and out of the brain via the lipoprotein receptor known as LRP – but this sometimes leaves the most dangerous substances in the brain to destroy cells. It’s a little bit like a police paddy wagon hauling away peaceful protesters while leaving behind the most violent offenders to work their mischief.

            Many of the ideas pioneered by Zlokovic are being explored further at Socratech Laboratories, a company he founded in 2000. The Small Business Innovation Research (SBIR) program recently awarded three grants worth a total of $300,000 to the company to explore the connections between the brain’s vascular system and Alzheimer’s disease. While healthy people continually grow new blood vessels, like an evolving supply line, to meet the brain’s need for oxygen and nutrients, the system slows or stops in patients with the disease. Socratech scientists are tracking the genes that direct the formation and growth of new blood vessels in the brain in a bid to possibly boost blood flow in patients with the disease. They’re also studying the genes responsible for a phenomenon doctors call “cerebrovascular senescence,” when blood flow plummets.

            In addition to Alzheimer’s disease, Zlokovic’s research also has implications for the health of the brain after a stroke. His team has been investigating why a drug known as TPA, which dramatically reduces the effects of stroke in some patients by restoring blood flow, actually kills some neurons. In the last decade he has published a series of papers showing that a compound now used to treat sepsis, Activated Protein C or APC, holds great promise in protecting brain cells from the damage caused by stroke and TPA.

            Zlokovic, who joined the University in 2000, is professor in the Department of Neurosurgery and director of the Frank P. Smith Laboratories for Neurosurgical Research. While he has been funded continuously by NIH for several years, the MERIT award – for “Method to Extend Research in Time” – gives him stable long-term funding, so he doesn’t have to hunt constantly for new funds to continue his work, as most researchers do.

            An acclaimed singer who turned down a career in opera for a career in medicine – and who then opted to use his knowledge to do basic research rather than treat patients directly – Zlokovic is upbeat about the opportunities that research presents to improve the health of patients worldwide.

            “Research is important for the new ideas that come along,” he says. “Whether the ideas are right or wrong, you always learn something new, and that knowledge oftentimes leads to breakthroughs that you couldn’t have predicted at the outset.”

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