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By blocking the activity of a protein with antibodies, researchers at the Stanford University School of Medicine were able to improve cognitive behavior in aging mice.
An article describing the results will be published online on April 3 in Nature. Tony Wyss-Coray, PhD, Professor of Neurology and Neurological Sciences, is the lead author. The lead author is John Pluvinage, a doctoral student in medicine.
Wyss-Coray has been working for several years on the question of what causes the loss of brain acuity with age. Her research has focused on a clbad of brain cells called microglia, which serve as both brain immune cells and waste management teams. To keep the brain healthy, microglia removes cellular debris and protein deposits that accumulate during a normal metabolic activity.
On average, the performance of microglia in waste collection decreases in aging brains. Why does this occur and to what extent is the faulty garbage service really responsible for age-related cognitive losses, is not clear. But it's a reasonable bet that one way or another, microglial malperformance plays a role in neurodegeneration, said Wyss-Coray, DH Chen II Full Professor and career researcher in the Palo Alto Health System. 'Veterans.
"Many genes whose high-risk variants have recently been linked to Alzheimer's disease are known to be active in the brain only in microglia," he said. "The patterns of microglial gene activation are abnormal in patients with Alzheimer's and in other neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis.
"We think we may have found a way to put these cells back on track and make them work as before."
The procedure of ingestion and then digestion, used by microglia and other types of immune cells in the body is called phagocytosis. The study used laboratory techniques to identify mouse genes whose activity alters or improves microglial phagocytosis and whose activity levels increase or decrease significantly with age.
Blocking the functionality of genes
The researchers selected about 3,000 genes encoding proteins that they thought could be targeted by drugs or had already been drug-developed. One at a time, they blocked the ability of each gene to encode a protein. The goal was to learn how each blockage affected the ability of mice to ingest microglia in culture to ingest small fluorescently labeled latex particles. (The more a microglial cell shone, the better was the garbage man.)
"It was like looking at the books of the trucking company," said Wyss-Coray. "We wanted to know:" Are these the defective wheels of the garbage truck? Rusty containers? An unexpected overflow of garbage? Lazy or poorly trained staff? Or is the street in poor condition? "
In a parallel experiment, the researchers determined which of these approximately 3,000 genes is more or less active in the hippocampal microglia of young mice compared to older mice. (The hippocampus is a brain structure, one on each side of the brain, essential for learning and memory.)
Surprisingly, when the scientists compared the results of the two experiments, they discovered a single gene that affected microglial phagocytosis and whose activity in microglia increased significantly with age. Older microglia produced much more copies of this gene – a substitute for the regulated production of the protein for which the gene is a model – than the younger ones, and neutralizing its function significantly improved microglial phagocytosis.
"We now have a suspect, a gene that had never been involved before in microglial garbage removal," said Wyss-Coray. So they targeted this gene, called CD22, which is found in both mice and humans.
In a subsequent experiment, the CD22 protein appeared three times more often on the surface of the microglia of older mice than on that of the microglia of younger mice, thus confirming the discovery of the activity of the gene. These proteins could be blocked by antibodies, molecules that bind to a specific protein and can be generated in the laboratory. Antibodies are bulky and do not penetrate easily into cells, but they are excellent at targeting cell surface proteins.
Injection of antibodies
The Wyss-Coray team injected anti-CD22 antibodies into the hippocampus on one side of the mouse brain. They also injected similar antibodies unable to bind to CD22 in the hippocampus on the opposite side.
In addition to the antibodies, the scientists administered fluorescently labeled myelin bits. This substance covers many nerve cells, for which it provides isolation. But myelin debris accumulates in aging brains and there is evidence that they exceed the ability of microglia to eliminate them.
Wyss-Coray and his badociates discovered that 48 hours later, the myelin fragments that they had injected into the hippocampus of the mouse were much less present on the side where they had administered CD22 blocking antibodies rather than "dummy" antibodies.
"Microglia is the only mouse brain cell that actually expresses the CD22 protein.This difference is probably due to the effect of anti-CD22 antibodies on microglia," Pluvinage said.
The researchers conducted similar experiments by substituting a protein called beta-amyloid, whose accumulation in the brain is a hallmark of Alzheimer's disease, and alpha-synuclein, another badociated protein. similarly to Parkinson's disease. In both cases, microglia exposed to CD22 blocking antibodies outperformed their peers on the opposite side of the brain by ingesting neurodegenerative substances.
Then, the researchers extended the exposure period from 48 hours to a full month. They reconfigured their injection technique to provide continuous infusion of CD22 blocking antibody on both sides of the brain during this time. The Wyss-Coray team found that older mice receiving these infusions performed better than age-matched mice at two different tests of learning and memory commonly used to badess their cognitive abilities.
"The mice have become smarter," said Wyss-Coray. "Blocking CD22 on their microglia has restored their cognitive function in younger mice, and CD22 is a new target that we believe can be exploited for the treatment of neurodegenerative diseases."
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