CD22 Antibodies Enhance Microglial Function and Cognitive Function in Mice
One of the many jobs undertaken by microglia in the central nervous system is to clean up pathogens, cell debris, and other molecular waste, ingesting it and breaking it down. Microglia become less capable with age, which is at least in part attributed to the more inflammatory environment characteristic of older individuals, but there are probably other significant causes. These cells do not replicate, and so are most likely more vulnerable to the accumulation of molecular damage than most cell populations.
In particular, this and other forms of stress can lead to cellular senescence, and senescent microglia have now been implicated in the progression of Parkinson's disease and Alzheimer's disease. The advent of senolytic therapies to selectively destroy senescent cells may turn out to produce significant benefits to patients with these and other neurodegenerative conditions. Of note, cellular senescence causes issues in part because these errant cells produce inflammatory signaling that rouses and disrupts the immune system, including other microglia. Cause and effect in the brain can be quite circular and confusing.
The ingest-then-digest procedure employed by microglia and other immune cell types in the body is called phagocytosis. A new study used laboratory techniques to identify mouse genes whose activity either impairs or enhances microglial phagocytosis and whose activity levels either increase or decrease substantially with age. The investigators picked about 3,000 genes encoding proteins that they judged could be targeted by drugs or that had already been the focus of drug development. The goal was to learn how each blockade affected the ability of cultured mouse microglia to ingest small particles of latex. One at a time, they blocked each gene's ability to encode a protein. In a parallel experiment, the investigators determined which of those approximately 3,000 genes are more or less active in microglia from the hippocampi of young mice versus old mice.
Surprisingly, when the scientists compared the results of both experiments, they found just one gene that affected microglial phagocytosis and whose activity in microglia substantially changed with advancing age. Older microglia produced far more copies of this gene - a proxy for upregulated production of the protein for which the gene is a blueprint - than younger ones did, and knocking out its function greatly improved microglial phagocytosis. So they zeroed in on this gene, called CD22, which is found in both mice and humans. In a follow-on experiment, the CD22 protein turned up three times as often on the surface of older mice's microglia as on those of younger mice's microglia, confirming the gene-activity finding. These proteins could be blocked by antibodies, molecules that bind to a specific protein and can be generated in the lab. Antibodies are bulky and don't easily penetrate cells, but they're excellent for targeting cell-surface proteins.
The team injected antibodies to the CD22 protein into the hippocampus on one side of mice's brains. Along with the antibodies, the scientists administered bits of myelin. This substance coats numerous nerve cells, for which it provides insulation. But myelin debris accumulates in aging brains and has been shown to overwhelm microglia's ability to clear it away. The researchers found that, 48 hours later, the myelin bits they'd injected into the mice's hippocampi were far less prevalent on the side where they had administered CD22-blocking antibodies. The investigators conducted analogous experiments, substituting a protein called beta-amyloid, whose buildup in the brain is a hallmark of Alzheimer's disease, and alpha-synuclein, another protein similarly associated with Parkinson's disease. In both cases, microglia exposed to CD22-blocking antibodies outperformed their peers in ingesting the neurodegeneration-linked substances.
The team observed that old mice receiving these infusions outperformed control mice of the same age on two different tests of learning and memory that are commonly used to assess mice's cognitive ability. "The mice became smarter. Blocking CD22 on their microglia restored their cognitive function to the level of younger mice. CD22 is a new target we think can be exploited for treatment of neurodegenerative diseases."