New Technique Removes Toxic Protein and Prevents Memory Impairment in Alzheimer's Disease Model
Increasing the activity of a key protein in the bloodstream slows the buildup of a toxic substance in the brains of mice with the gene mutation for Alzheimer's disease (AD). It also prevents some memory problems, a new study shows. If the approach works in humans, it may eventually lead to a way of preventing or halting AD.
Previous studies have shown that a protein called amyloid beta is toxic to neurons. Amyloid beta accumulates in the brains of people with AD, forming deposits called amyloid plaques that are a hallmark of the disease. Many investigators are looking for ways to reduce the buildup of amyloid in the brain, with the hope that such a treatment would slow or halt AD.
In the new study, investigators report a way to remove amyloid beta from the brain by introducing another protein that binds to amyloid beta and pulls it from the bloodstream. The amyloid is then removed by the kidneys, liver, and spleen. The investigators, led by Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center in New York, compare the treatment to a sink because it essentially drains the toxic protein away. The work was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS). It is reported in
Dr. Zlokovic and his colleagues studied a protein called soluble low-density lipoprotein receptor-related protein (sLRP). They discovered that sLRP normally binds to and inactivates 70 to 90 percent of the amyloid beta found in the body. However, levels of sLRP were approximately 30 percent lower in blood from people with AD than in healthy people. Much of the remaining sLRP in people with AD was damaged by a process called oxidation. The damaged sLRP was much less effective at removing amyloid beta from the bloodstream than the normal protein. "The binding capability is almost all lost," Dr. Zlokovic says.
The researchers developed a super-potent version of sLRP, called LRP-IV, and injected it into mice to see whether it could mimic the effects of normal sLRP. The treatment bound to amyloid beta and prevented it from entering the brain. It also reduced the toxic amyloid that was already in the brain.
“There is a balance between amyloid beta in the brain and in the rest of the body,” Dr. Zlokovic explains. “If we lower the level of amyloid beta circulating in the blood, the levels in the brain go down, too.” The effect is similar to the way statin drugs remove cholesterol from the bloodstream and help to prevent heart disease, he adds.
The investigators also studied the effects of chronic low-dose LRP-IV treatment in mice with a gene mutation that causes AD in humans. The treatment began when the mice were six months old and continued every day for three months. At the end of the treatment period, the mice that received LRP-IV had much less amyloid beta in their brains and their bloodstreams than untreated mice, and they performed nearly as well as normal mice on several tests of learning and memory. Even when treatment began at 11 months, when the mutant mice had many amyloid-related brain changes, LRP-IV reduced amyloid deposits in the brain and blood vessels by more than 90 percent.
The researchers also cultured LRP-IV with blood samples from people with AD and found that the treatment eliminated toxic amyloid from the blood samples.
The study is the first to show that people with AD have reduced levels of sLRP and that sLRP helps remove amyloid beta from the blood, Dr. Zlokovic says. It is still unclear why sLRP levels are lower than normal in people with the disease, he adds. The researchers tested 40 people with AD for mutations in the sLRP gene and did not find any abnormalities. However, previous studies have shown that AD causes oxidative damage to many proteins. The oxidative damage to sLRP may trigger its breakdown, as well as inactivating it.
The findings suggest that LRP-IV might eventually be useful as a therapy to prevent or stop AD in people. However, the investigators first need to develop a form of the protein that could be tested in humans. They also need to conduct many additional studies to evaluate the drug’s safety and to learn more about how it works.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs,
-By Natalie Frazin
Previous studies have shown that a protein called amyloid beta is toxic to neurons. Amyloid beta accumulates in the brains of people with AD, forming deposits called amyloid plaques that are a hallmark of the disease. Many investigators are looking for ways to reduce the buildup of amyloid in the brain, with the hope that such a treatment would slow or halt AD.
In the new study, investigators report a way to remove amyloid beta from the brain by introducing another protein that binds to amyloid beta and pulls it from the bloodstream. The amyloid is then removed by the kidneys, liver, and spleen. The investigators, led by Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center in New York, compare the treatment to a sink because it essentially drains the toxic protein away. The work was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS). It is reported in
Dr. Zlokovic and his colleagues studied a protein called soluble low-density lipoprotein receptor-related protein (sLRP). They discovered that sLRP normally binds to and inactivates 70 to 90 percent of the amyloid beta found in the body. However, levels of sLRP were approximately 30 percent lower in blood from people with AD than in healthy people. Much of the remaining sLRP in people with AD was damaged by a process called oxidation. The damaged sLRP was much less effective at removing amyloid beta from the bloodstream than the normal protein. "The binding capability is almost all lost," Dr. Zlokovic says.
The researchers developed a super-potent version of sLRP, called LRP-IV, and injected it into mice to see whether it could mimic the effects of normal sLRP. The treatment bound to amyloid beta and prevented it from entering the brain. It also reduced the toxic amyloid that was already in the brain.
“There is a balance between amyloid beta in the brain and in the rest of the body,” Dr. Zlokovic explains. “If we lower the level of amyloid beta circulating in the blood, the levels in the brain go down, too.” The effect is similar to the way statin drugs remove cholesterol from the bloodstream and help to prevent heart disease, he adds.
The investigators also studied the effects of chronic low-dose LRP-IV treatment in mice with a gene mutation that causes AD in humans. The treatment began when the mice were six months old and continued every day for three months. At the end of the treatment period, the mice that received LRP-IV had much less amyloid beta in their brains and their bloodstreams than untreated mice, and they performed nearly as well as normal mice on several tests of learning and memory. Even when treatment began at 11 months, when the mutant mice had many amyloid-related brain changes, LRP-IV reduced amyloid deposits in the brain and blood vessels by more than 90 percent.
The researchers also cultured LRP-IV with blood samples from people with AD and found that the treatment eliminated toxic amyloid from the blood samples.
The study is the first to show that people with AD have reduced levels of sLRP and that sLRP helps remove amyloid beta from the blood, Dr. Zlokovic says. It is still unclear why sLRP levels are lower than normal in people with the disease, he adds. The researchers tested 40 people with AD for mutations in the sLRP gene and did not find any abnormalities. However, previous studies have shown that AD causes oxidative damage to many proteins. The oxidative damage to sLRP may trigger its breakdown, as well as inactivating it.
The findings suggest that LRP-IV might eventually be useful as a therapy to prevent or stop AD in people. However, the investigators first need to develop a form of the protein that could be tested in humans. They also need to conduct many additional studies to evaluate the drug’s safety and to learn more about how it works.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs,
-By Natalie Frazin
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