Discovery may yield Alzheimer's advance

Zlokovich

esearchers have made a promising discovery into how a toxic protein destroys brain cells in Alzheimer's patients. In the study, led by Berislav Zlokovic, professor of neurological surgery, researchers were able to virtually block the flow of the protein into the brains of mice and consequently reduce protein accumulations in the brain by more than 70 percent. The results were featured in the July 1 issue of Nature Medicine.

"For more than a decade we've known that this protein wreaks havoc in the brains of Alzheimer's patients, but we haven't known how it gets there or how to prevent it from getting there. This study answers both of those basic questions and opens an entirely new avenue for the treatment of Alzheimer's disease," says Zlokovic.

The new findings center on amyloid beta, a tiny protein molecule that accumulates over time to form tell-tale plaques in the brain tissue of Alzheimer's patients. The study reveals for the first time how the protein gets from the blood into the brain, thwarting the brain's elaborate filtration mechanism that normally keeps away toxins.

Since 1992, Zlokovic's research has focused on how amyloid beta protein in the blood is able to pass through the blood-brain barrier, a thin layer of cells that lines the inner walls of the brain's blood vessels. In the current study, Zlokovic and his colleagues found that amyloid beta protein molecules cannot flow through the blood-brain barrier unaided. Rather, the molecules get through by riding piggyback on a much larger molecule, called RAGE, (short for receptor for advanced glycation end products), which is nontoxic and moves unfettered across the blood-brain barrier.

The researchers also found that as RAGE transported increased levels of amyloid beta into the brain, blood flow within the brain was reduced by half. However, when soluble RAGE, a look-alike molecule that cannot pass through the blood-brain barrier, was administered to block the process, blood flow to the brain returned to normal.

"The experiments in this study revealed a great deal of new information about Alzheimer's disease," says Zlokovic. "First, it is now very clear that the body regulates the movement of amyloid beta proteins across the blood-brain barrier. Second, we've shown that we can use a drug to stop the flow of amyloid beta from the blood to the brain. Finally, we learned that when we block the flow of amyloid beta over time, the brain substantially rids itself of amyloid beta and the amyloid plaques shrink dramatically.

"For patients with Alzheimer's disease, these findings suggest that we can develop a new class of drugs that work by blocking the flow of the toxic Alzheimer's protein into the brain," adds Zlokovic.

The researchers are looking ahead to clinical trials of new drug candidates. They are planning studies to determine whether soluble RAGE is likely to be safe when administered to people and are working to identify other molecules that work in the same way.

Collaborators in the study, which was funded by a grant from the National Institutes of Health, included Mark Kindy from the University of South Carolina and David Stern and Shi Du Yan from Columbia University.

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