NIH Research Matters
August 27, 2007
Soaking up Toxic Protein to Stop Alzheimer's Disease
Scientists have come up with a potential new treatment strategy for Alzheimer's disease (AD): Prevent the buildup of a toxic protein in the brain by soaking the protein up in the bloodstream and letting the body clear it away.
AD is characterized by a large number of dense protein deposits, called plaques, that surround nerve cells in the brain. Made of a protein called amyloid-beta, these plaques are found in the hippocampus, a structure important for memories, and in other areas of the brain used in thinking and decision-making. Scientists still aren't sure whether these amyloid-beta plaques cause AD, but most agree that they are toxic to brain cells and contribute to the symptoms seen in AD patients. Much of the research aimed at developing treatments for AD focus on removing plaques or preventing their formation.
Over the last 10 years, scientists have made significant progress in understanding how amyloid-beta proteins move into and out of the brain. A research team led by Dr. Berislav Zlokovic from the University of Rochester Medical Center reasoned that they might be able to lower the amount of amyloid-beta that entered the brain if they could decrease the level of protein in the blood. Previous research showed that a protein called lipoprotein receptor-related protein-1 plays a key role in clearing amyloid-beta from the body. Other researchers found a form of the protein, called soluble lipoprotein receptor-related protein-1 (sLRP), in the blood. With funding from NIH's National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS), the team set out to explore whether alterations in sLRP could affect the development of AD.
The researchers reported in the online edition of Nature Medicine on August 12, 2007, that sLRP binds 70-90% of the amyloid-beta protein in healthy people. People with AD had 20-30% less sLRP in their blood than healthy people. Further, the sLRP protein in patients with AD was almost 3 times as likely to be damaged as in healthy people. As a result, patients with AD had 3-4 times more free amyloid-beta circulating in their bloodstream than healthy people.
The scientists next synthesized an altered version of sLRP, called LRP-IV, that binds to amyloid-beta protein much better than natural sLRP. They tested LRP-IV in mice that were genetically altered to develop symptoms similar to AD at about 11 months of age. When the mice were treated before the onset of symptoms, at 6 months of age, their learning and memory were improved. The results were even more dramatic when the mice were treated after they had begun to develop symptoms. Treating 11-month old mice with LRP-IV for 6 weeks improved their learning and memory and reduced the amyloid-beta plaques in their brains by over 90%.
In mouse models of AD, plaques appear in blood vessels before they can be detected in the brain. The researchers showed that LRP-IV could remove amyloid-beta from the blood of the mice and prevent the formation of plaques in blood vessels. They also showed it can clear amyloid-beta from blood plasma withdrawn from people with AD. With further development, enhanced versions of sLRP may prove to be an effective tool for treating people with AD.— by Deborah Stewart, Ph.D.
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NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.