Published on: October 7, 2014
by Andrew Tobin for The Times of Israel:
Studying mice, Israeli scientists have discovered that as the brain ages, it may become cut off from the immune system, possibly contributing to cognitive decline ranging from increased forgetfulness to dementia.
In a study recently published in the journal Science, the researchers found that old mice had elevated levels of a unique protein in the lining between their brains and their blood supply. This protein, they found, seemed to block the mice’s immune systems from supporting their brains, impairing their cognitive abilities. The scientists were able to partially restore these abilities by neutralizing the protein.
They also found that the suspect protein, called interferon beta, appeared to be expressed at similarly high levels in the lining, called the choroid plexus, of elderly human cadavers. The findings could one day lead to treatments to slow or even to reverse cognitive decline associated with aging in people, the scientists say.
“Immune cells in the choroid plexus respond to distress signals from the brain by expressing molecules associated with tissue maintenance and neuron creation in the brain,” said Prof. Michal Schwartz, a neuroimmunolgist at the Weizmann Institute of Science, who led the study along with Dr. Ido Amit, an immunologist at the institute.
“When we are young, the system works very well like that. But as we are aging, the distress signal causes a buildup of interferon beta at the site where the brain meets the blood, preventing the brain from recruiting immune assistance.”
Graduate students Kuti Baruch and Aleksandra Deczkowska coauthored the study. The research is in its beginning stages, far from human applications.
Though largely a scientific mystery, aging can lead to a loss of brain function, causing problems with cognitive abilities, like memory, language, thinking, and judgment. Mild cognitive impairment and dementia, caused by Alzheimer’s disease or other neurological conditions, become more common with age.
For many years, it was scientific dogma that the brain functions best when it is shielded from the immune system. But in a decade of ground-breaking research, Schwartz has shown that the immune system actually plays an important role in brain health — promoting the development of new neurons and helping to maintain normal brain functioning.
In a study last year, Schwartz suggested that the brain and the immune system interact via the choroid plexus. When the brain has an “emergency” — which can be as minor as a stressful event or as serious as a traumatic injury — it calls the choroid plexus for help, and the choroid plexus dutifully sends molecules to support it, her study indicated.
“The choroid plexus serves as a mediator, allowing immune cells to interact with the brain, without necessarily letting them get inside. These immune cells sitting in the choroid plexus produce molecules that trigger the choroid plexus to produce goodies needed for the brain,” said Schwartz.
Given this interaction, Schwartz had suspected that changes in immune function throughout life contribute to changes in brain function.
To test this theory, the scientists sequenced the RNA of both old and young mice in 11 organs, including in the choroid plexus. By comparing gene expression in the two groups of mice, they found a unique “aging signature” in the choroid plexuses of the old mice. A major feature of the signature was much higher expression of interferon beta, which normally happens when the body is fighting viruses and inflammation, than in the young mice.
In addition, the old mice’s choroid plexuses were less supportive of the movement of immune cells to the brain, biochemical analysis of both groups of mice revealed. Injecting the brain fluid of old mice with an antibody that blocks interferon beta activity made their choroid plexus more supportive of immune cell movement boosted the formation of new neurons in the brain, measured by biochemical analysis. The injection also partly reversed cognitive decline in the old mice, restoring their cognitive abilities to younger levels.
Based on previous research, Schwartz suggests that interferon beta is expressed as part of the choroid plexus response to emergency calls from the brain. When the choroid plexus is called on too often or for too long, she says, interferon beta likely builds up there and prevents the choroid plexus from helping the brain.
“If the choroid plexus is signaled continuously, its activity gets disrupted,” said Schwartz.
Analysis of the choroid plexus of elderly human cadavers revealed a similar aging signature, including elevated interferon beta levels, suggesting that the same process of blockage occurs in people. This process, along with normal cellular aging, could explain cognitive decline in people as they age, the scientists say — though more research is needed to rule out the influence of other factors.
On the plus side, they say, treatments that target interferon beta expression or activity could one day be developed to keep the choroid plexus “young.” A younger choroid plexus could mean a younger brain, at lower risk of mild cognitive impairment and dementia.
Picture: Immunofluorescence microscopy image of the brain’s choroid plexus. (photo credit: Kuti Baruch and Aleksandra Deczkowska)
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