Nov. 7, 2000 Scientists have discovered how mice normally sweep away the protein that forms the plaques in brain tissue that are a hallmark of Alzheimer's disease. The findings point to blood circulation in the brain as playing a key role in the prevention of the beta amyloid plaques that speckle the brains of Alzheimer's patients, and should help scientists better understand how the plaques accumulate and perhaps how to prevent them.
In a study in mice, a team led by neurosurgeon Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center found that blood vessels are responsible for removing the beta amyloid protein in healthy brain tissue. Zlokovic's team found that the endothelial cells that line the blood vessels are key to the process. In particular, a protein known as LRP-1 (low density lipoprotein receptor-related protein), a molecule that plays a role in the transport and metabolism of lipids such as cholesterol, rapidly shuttles beta amyloid out of the brain and across the blood-brain barrier to the body, which breaks it down into harmless waste products.
Amyloid deposits in the brain are one of the classic signs of Alzheimer's disease. Most scientists agree the deposits are toxic to brain cells, causing the neurodegenerative damage seen in Alzheimer's patients, while some believe the deposits are a byproduct of a more basic disease process. Either way, neurons die, and removing plaques or preventing their formation is a line of research pursued by many physicians and scientists.
Zlokovic's team injected amyloid peptide into the brains of mice, blocked various molecules in the bloodstream, then monitored the blood to see how well the proteins were being removed from the brain. They found that when LRP-1 was blocked, the removal of amyloid from the brain slowed dramatically. They also showed that healthy middle-aged mice 9 to 12 months old had fewer LRP-1 molecules in their blood vessels, and that these mice shuttled amyloid out of their brains at only half the rate as young mice.
The results mark the first time scientists have shown that the vascular system has a role in removing plaques from the brain. Zlokovic says it's likely that amyloid peptide is constantly present in the brain but that in healthy young animals and people, blood vessels constantly remove it, ferrying it away from the brain cells that it can damage.
"The idea that healthy people have small amounts of amyloid peptide in their brains, and that somehow the body is constantly neutralizing it, has been around for awhile," says Zlokovic. "But just how the body takes care of it has been a big question mark." Scientists have known that neurons themselves can clear small amounts of amyloid from the brain, but Zlokovic says blood vessels remove the protein 50 to 100 times faster, doing in just half an hour what takes neurons days to remove. It's the fastest known handling of amyloid by any molecule or process in the body.
"Neurons are responsible for thinking, not for cleaning," says Zlokovic. "Neurons help us think, move, survive, and make functional circuits. It would really be a waste of energy if the body depended on them to keep the brain clean from wastes."
Blood vessels routinely supply nutrients like oxygen and sugar to the brain, and they remove waste products like carbon dioxide. It's no surprise to Zlokovic, a vascular neurosurgeon, that the blood is also involved in removing toxic plaques from the brain. Zlokovic suspects that healthy young people normally can handle the load of removing amyloid, but that plaques can occur when the LRP-1 system becomes less efficient and the body faces other challenges related to aging, such as decreased circulation. It's also possible that the protein begins accumulating more quickly, overwhelming the removal system. In the study, even healthy young animals had difficulty removing proteins at levels found in Alzheimer's disease.
"The slowdown of the amyloid-removal process is not a problem if everything else is functioning perfectly," says Zlokovic. "But if there's any other problem, the material begins accumulating, and the chance of the body successfully removing amyloid from the brain becomes less and less."
LRP-1 plays an important role in the metabolism of lipids and supplies fat to neurons, which need it to keep healthy and to send electrical impulses along the nerves they form. The team found that LRP-1, part of the family of proteins that handle "bad cholesterol," seems to work closely with two other proteins, alpha-2-macrolglobulin and apolipoprotein E (apoE), a protein known to be involved in some forms of Alzheimer's disease.
Zlokovic, chief of the Division of Neurovascular Biology at the University of Rochester's Center for Aging and Developmental Biology, performed much of this research at the University of Southern California (USC) before coming to Rochester this summer. Also taking part in the project were researchers at USC, New York University Medical Center, and Washington University School of Medicine.
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