Early brain effects of HIV in mouse model

ScienceDaily (Mar. 2, 2011) — A new mouse model closely resembles how the human body reacts to early HIV infection and is shedding light on nerve cell damage related to the disease, according to researchers funded by the National Institutes of Health.

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The study in the Journal of Neuroscience demonstrates that HIV infection of the nervous system leads to inflammatory responses, changes in brain cells, and damage to neurons. This is the first study to show such neuronal loss during initial stages of HIV infection in a mouse model.

The study was conducted by a team of scientists from the University of Nebraska Medical Center, Omaha, and the University of Rochester Medical Center, N.Y. It was supported by the National Institute on Drug Abuse (NIDA), the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Center for Research Resources.

"This research breakthrough should help us move forward in learning more about how HIV affects important brain functioning in its initial stages, which in turn could lead us to better treatments that can be used early in the disease process," said Dr. Nora D. Volkow, director of NIDA.

"The work contained within this study is the culmination of a 20-year quest to develop a rodent model of the primary neurological complications of HIV infection in humans," said Dr. Howard Gendelman, one of the primary study authors. "Previously, the rhesus macaque was the only animal model for the study of early stages of HIV infection. However, its use was limited due to expense and issues with generalizing results across species. Relevant rodent models that mimic human disease have been sorely needed."

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Multiple sclerosis blocked in mouse model: Barring immune cells from brain prevents symptoms

ScienceDaily (Mar. 7, 2011) — Scientists have blocked harmful immune cells from entering the brain in mice with a condition similar to multiple sclerosis (MS).

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According to researchers from Washington University School of Medicine in St. Louis, this is important because MS is believed to be caused by misdirected immune cells that enter the brain and damage myelin, an insulating material on the branches of neurons that conduct nerve impulses.

New insights into how the brain regulates immune cell entry made the accomplishment possible. Washington University scientists had borrowed an anti-cancer drug in development by the company ChemoCentryx simply to test their theories.

"The results were so dramatic that we ended up producing early evidence that this compound might be helpful as a drug for MS," says Robyn Klein, MD, PhD, associate professor of pathology and immunology, of medicine and of neurobiology. "The harmful immune cells were unable to gain access to the brain tissue, and the mice that received the highest dosage were protected from disease."

ChemoCentryx is now testing the drug in Phase I safety trials. The study is published in The Journal of Experimental Medicine.

Klein and her colleagues discovered a chemical stairway that immune cells have to climb down to enter the brain. Immune cells that exit the blood remain along the vessels on the tissue side, climbing down from the meninges into the brain where they can then cross additional barriers and attack myelin on the branches of neurons.

"The effect of immune cell entry into the brain depends on context," Klein says. "In the case of viral infection, immune cell entry is required to clear the virus. But in autoimmune diseases like multiple sclerosis, their entry is associated with damage so we need to find ways to keep them out."

The stairway is located on the tissue side of the microvasculature, tiny vessels that carry blood into the central nervous system. The steps are made of a molecule called CXCL12 that localizes immune cells, acting like stairs that slow them down so that they can be evaluated to determine if they are allowed to enter the brain. Klein's lab previously discovered that the blood vessel cells of the microvasculature display copies of this molecule on their surfaces.

Klein also found that MS causes CXCL12 to be pulled inside blood vessel cells in humans and mice, removing the stairway's steps and the checkpoints they provide. In the new paper, she showed that blocking the internalization of the molecule prevented immune cells from getting into the brain and doing harm.

Work by another lab called Klein's attention to CXCR7, a receptor that binds to CXCL12. She showed that the receptor is made by the same cells in the microvasculature that display CXCL12. They watched the receptor take copies of CXCL12 and dump them in the cells' lysosomes, pockets for breakdown and recycling of molecules the cell no longer needs.

"After it dumps its cargo in the lysosome, the receptor can go right back to the cell surface to pull in another copy of CXCL12," Klein says. "There likely exists an equilibrium between expression and disposal of CXCL12. Some of the proteins expressed by the immune cells in MS patients affect CXCR7 expression and activity, disrupting the equilibrium and stripping the steps from this immune cell stairway we're studying."

Klein contacted researchers at ChemoCentryx, who were developing a blocker of the CXCR7 receptor as a cancer treatment. When they gave it to the mouse model of MS, immune cells stopped at the meninges.

Klein also found that immune factors could cause microvasculature cells to make more or less of CXCR7, ramping up or down the number of steps on the chemical stairway. She is currently investigating additional immune factors that impact on CXCR7 activity within the blood vessel cell. Whether a given factor promotes or suppresses the receptor may also differ depending upon what part of the brain is being considered.

"One of the biggest questions in MS has been why the location, severity and progression of disease varies so much from patient to patient," Klein says. "Getting a better understanding of how these factors regulate immune cell entry will be an important part of answering that question."

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Vehicle pollution significantly damages the brain, mouse study suggests

ScienceDaily (Apr. 13, 2011) — If mice commuted, their brains might find it progressively harder to navigate the maze of Los Angeles freeways. A new study reveals that after short-term exposure to vehicle pollution, mice showed significant brain damage -- including signs associated with memory loss and Alzheimer's disease.

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The mind-numbing toxin is not an exhaust gas, but a mix of tiny particles from burning of fossil fuel and weathering of car parts and pavement, according to the study to be published April 7 in the journal Environmental Health Perspectives.

Many studies have drawn a link between vehicle pollution and health problems. This is the first to explore the physical effect of freeway pollution on brain cells.

The authors found a way to recreate air laden with freeway particulate matter inside the laboratory. Whether in a test tube or in live mice, brain cells showed similar responses:

Neurons involved in learning and memory showed significant damage, The brain showed signs of inflammation associated with premature aging and Alzheimer's disease, Neurons from developing mice did not grow as well.

The freeway particles measured between a few dozen to 200 nanometers -- roughly one-thousandth the width of a human hair, and too small for car filtration systems to trap.

"You can't see them, but they are inhaled and have an effect on brain neurons that raises the possibility of long-term brain health consequences of freeway air," said senior author Caleb Finch, an expert in the effects of inflammation and holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging.

Co-author Constantinos Sioutas, of the USC Viterbi School of Engineering, developed the unique technology for collecting freeway particulates in a liquid suspension and recreating polluted air in the laboratory. This made it possible to conduct a controlled study on cultured brain cells and live animals.

Exposure lasted a total of 150 hours, spread over 10 weeks, in three sessions per week lasting five hours each.

"Of course this leads to the question, 'How can we protect urban dwellers from this type of toxicity?' And that's a huge unknown," Finch said.

The authors hope to conduct follow-up studies on issues such as:

Memory functions in animals exposed to freeway particulates, Effects on development of mice exposed prenatally, Lifespan of exposed animals, Interaction of particulates with other components of smog, such as heat and ozone, Potential for recovery between periods of exposure, Comparison of effects from artificially and naturally occurring nanoparticles, Chemical interactions between freeway particulates and brain cells.

If further studies confirm that freeway particulates pose a human health hazard, solutions will be hard to find.

Even an all-electric car culture would not solve the problem on its own, Finch said.

"It would certainly sharply decrease the local concentration of nanoparticles, but then at present electrical generation still depends upon other combustion processes -- coal -- that in a larger environment contribute nanoparticles anyway.

"It's a long-term global project to reduce the amount of nanoparticles around the world. Whether we clean up our cars, we still have to clean up our power generation."

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