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Mice are not people, but like us, they become forgetful in old age. In a study published online May 13 in Nature MedicineOlder mice suffered much less senior moments during a battery of memory tests when investigators at Stanford University's School of Medicine neutralized a single molecule scattering the brain's cerebral blood vessels. For example, they crossed a labyrinth with a characteristic ease of young adult mice.
The molecule appears on the surface of a small percentage of endothelial cells, the main components of blood vessels throughout the body. Blocking the ability of this molecule to do its main job – it selectively locks on immune cells circulating in the blood – not only improves the cognitive performance of old mice, but counteracts two physiological features of the aging brain: it restores the capacity from the old brains of mice to create new nerve cells, and he subjected the inflammatory mood of resident immune cells of the brain, called microglia.
Scientists have shown that the blood of older mice is bad for the brains of these mice. Scientists strongly suspect that something in the blood of older people similarly causes a decline in brain physiology and cognitive skills. What this something is left to reveal. But, according to the new study, there may be a convenient way to block its passage between rubber and road: at the blood-brain barrier, which tightly regulates the passage of most cells and substances through the walls of vessels blood brain.
"We may have found an important mechanism by which blood communicates deleterious signals to the brain," said Tony Wyss-Coray, lead author of the study, professor of neurology and neurological sciences and co-director of the Center for Disease Control. Alzheimer's disease research from Stanford. and Principal Investigator in the Palo Alto Health System of Veterans Affairs. The lead author of the study is Hanadie Yousef, PhD, a former postdoctoral researcher at the Wyss-Coray laboratory.
The success of the intervention indicates possible treatments that could one day slow down, stop or even reverse this decline. It may be easier to target a protein on the walls of the blood vessels than to try to penetrate the brain itself.
"We can now try to treat brain degeneration by using drugs that are generally not very effective in crossing the blood-brain barrier – but, in this case, they would not need to do it anymore," he said. Yousef.
Another way to reach the brain
The researchers focused on the mouse hippocampus, a well-studied brain structure that is essential for memory and learning, and whose architecture and function are similar in mice and humans. The hippocampus is also one of the few adult mammalian brain sites where neurogenesis occurs, creating new nerve cells. these new cells are essential for the formation of new memories.
Since his lab began reporting several years ago that unknown factors in old blood could accelerate cognitive decline and, conversely, that factors in young blood rejuvenated old brains, Wyss-Coray, DH Chen Professor II, sought to identify these factors. But he and his colleagues took a different approach in the new study.
He added that the approximately 400 miles of blood vessels that pass through the human brain differ from those elsewhere in the body on an important point: they are much more selective about what goes in and out.
The blockage of VCAM1 in the brain eventually made these mice smarter.
"The blood-brain barrier excludes most blood-borne cells and substances," he said. "We wondered if, instead of entering the brain and singer directly with the brain cells, something in the circulating blood could directly communicate with the endothelial cells of the brain."
A few years ago, Wyss-Coray and her colleagues compared the blood of young and old to identify substances whose abundance changes with age. In the new study, they limited their search to only age-associated blood-borne substances that are in some way directly related to vascular function. At the top of the list was a circulating form of protein permanently produced in endothelial cells and displayed on their surface.
The protein, VCAM1, is well known to immunologists. It is a docking station for circulating cells of the immune system – a first stop in a passport perforation process that, under some relatively rare conditions, gives these immune cells permission to migrate across the border otherwise closed brain.
This protein is sawn from the surface of the endothelial cells and released into the blood by lawn mower-like enzymes at about the same rate of production, so that the size of its population on the blood vessels remains relatively constant. However, the abundance of VCAM1 on the surface of the blood vessels increases considerably in the event of injury or local infection. It catches immune cells, which fight infectious pathogens and are essential to the healing process.
"At all times, circulating levels of VCAM1 are a good indicator of the total amount of VCAM1 on the surface of endothelial cells of the body's blood vessels," said Wyss-Coray. Previous studies have associated high levels of circulating VCAM1 with cancer, heart disease, stroke, Alzheimer's disease, epilepsy and other inflammatory disorders.
Identify the source of the malfunction
In the study, the researchers showed that the abundance of VCAM1 on endothelial cells including the walls of blood vessels in the brain of mice grew in older age, as well as in the brains of younger mice receiving plasma infusions of older mice, the liquid portion of blood. Similarly, the researchers observed an increase in the signs of inflammation in the cells of older mice.
Wyss-Coray suspects that the attachment of immune cells to the surface of blood vessels – especially if immune cells are activated because of an existing condition, such as an injury or infection, or still at an advanced age – improves the release of inflammatory proteins that penetrate blood vessel walls via specialized receptors on the surface of endothelial cells.
The circulation of VCAM1, however, was not the source of brain dysfunction. When the researchers exhausted the protein plasma of aged mice before giving it to young mice, they observed the same adverse effects on the hippocampus – reduced neurogenesis, increased microglial inflammation – that they had already observed when young mice received old plasma.
The deletion of the gene coding for VCAM1 in mouse brains prevented the production of the protein in endothelial cells of the brain. If this was done in young adults, the mice no longer suffered from reduced neurogenesis or increased microglial inflammation with age.
The researchers obtained the same results with monoclonal antibodies, specialized proteins that bind greedily and exclusively to their target. Three weeks of treatment with a monoclonal antibody targeting and directly blocking VCAM1 were sufficient to increase neurogenesis and decrease microglial reactivity in the hippocampi of older mice.
These mice have undergone a battery of tests of mental acuity. A test, Barnes' labyrinth, involves a table on which the mice want to escape. The table has many holes through which the mouse can fall to the ground for a short distance (but not enough to cause injury). But a hole connects to a tube mounted horizontally under it, providing a comforting escape to the mice. The mouse must learn and remember how to get to the "security" hole.
After their training was completed, the aged mice treated with this antibody reached the vanishing hole of the Barnes labyrinth as rapidly as the young mice.
"The blockage of VCAM1 in the brain eventually made these mice smarter," said Wyss-Coray. "Since all that time I've been working on that, I've never seen such a performance before."
Wyss-Coray is a member of the Wu Tsai Neurosciences Institute at Stanford, the Stanford and Stanford Bio-X Institute for the Health of the Mother and Child, and a faculty member at Stanford University. Stanford CHEM-H.
Yousef is co-founder and CEO of Juvena Therapeutics, a biotechnology company. (Juvena Therapeutics is not pursuing the clinical use of VCAM-1 blocking agents.)
The other authors of the Stanford study are former postdoctoral fellows, Cathrin Czupalla, PhD, and Vidhu Mathur, PhD; research associate Davis Lee; postdoctoral Michelle Chen, PhD, Kristy Zera, PhD, and Todd Peterson, PhD; Ashley Burke, former undergraduate student; Judith Zandstra, former student researcher; former laboratory coordinator Elisabeth Berber, PhD; Benoit Lehallier, PhD, lecturer in neurology and neurological sciences; research engineer Ramesh Nair, PhD; Liana Bonanno, doctoral student in medicine; graduate student Andrew Yang; research scientist Husein Hadeiba, PhD; Taylor Merkel, undergraduate student; Associate Professor of Neurology and Neurological Sciences Marion Buckwalter, MD, PhD; Professor of Bioengineering and Applied Physics Stephen Quake, PhD; and professor of pathology Eugene Butcher, MD.
The work was funded by the National Institutes of Health (R01AG045034, DPAG053015, R01GM37734, R37AI047822, R01AI109452 and UL1TR001085); the Department of Veterans Affairs; the NOMIS Foundation; the Glenn Foundation for Research on Aging; D.H. Chen Foundation; the National Center for the Advancement of Translational Sciences; the Stanford Institute for Immunity, Transplantation and Infection; the Wu Tsai Neuroscience Institute; and the Edinger Institute.
Researchers from the University Medical Center Hamburg-Eppendorf and the University of Lübeck, both German, also contributed to the work.
The Department of Neurology and Neurological Sciences at Stanford also supported the work.
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