Blocking activity of a protein can restore cognitive ability in old mice

A study online published in Nature has shown that the ability to block the activity of a protein with antibodies can improve cognitive behavior in aging mice.

Tony Wyss-Coray, a senior author of the study, has been studying for years why the brain loses its acuity with age. He focuses on a class of brain cells called microglia, a type of glial cell, equivalent to macrophages in the brain and spinal cord. Microglia is the first and the most important immune defense line in the central nervous system (CNS). As a garbage worker, microglia constantly removes damaged nerves, plaques and infectious substances from the central nervous system. Many clinical and neuropathological studies have revealed that activated microglia play a crucial role in the pathogenesis of neurodegenerative diseases.

In general, the clearance ability of microglia in the aging brain is reduced. Why this phenomenon happens and the content to which these garbage obstacles actually cause age-related cognitive loss are still unknown. However, the poor performance of microglia is a good choice for neurodegenerative diseases.

High-risk variants of many genes have recently been found to be associated with Alzheimer's disease, but these genes are known to be active in the brain only in microglia. The activation pattern of microglia genes is abnormal in Alzheimer's disease patients and other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis.

Researchers at Stanford University School of Medicine have selected about 3,000 genes encoding proteins that may be drug targeting points or have become the focus of drug development. To understand how each blocker affects the ability of mouse cultured microglia to absorb fluorescently labeled latex particles, the researchers blocked the ability of each gene one at a time. It is known that the brighter the light emitted by microglia, the stronger its ability to remove garbage from the brain.

As the experiment progressed, the team found that only one gene, CD22, influenced the phagocytosis of microglia, and the activity of this gene in microglia increases significantly with age. Older microglia produce more copies of this gene than younger glial cells. This copy is a manifestation of the up-regulation of protein production in the blueprint of the gene, and its destruction greatly improved phagocytosis of microglia cells.

Therefore, they focused on the CD22 gene, which is present in both mice and humans. In subsequent experiments, CD22 protein appeared on the surface of microglia in aged mice three times as much as the surface of young mouse microglia, confirming the discovery of gene activity.

Next, the group respectively injected CD22 protein antibody and a similar antibody that could not bind to CD22 on two sides of the hippocampus of the mouse brain, together with a fluorescently edited myelin sheath. After 48 hours, the researchers observed that the myelin sheath in the side of the mouse hippocampus injected with CD22 protein antibody was much less than the other side.

Microglia are the only cells in the mouse brain that actually express CD22 protein, and these proteins can be blocked by antibodies, and antibody molecules bind to specific proteins. Antibodies are bulky and difficult to penetrate cells, but they are very effective at targeting cell surface proteins.

The researchers conducted a similar experiment, replacing a protein called beta-amyloid and alpha-synuclein. The accumulation of beta-amyloid in the brain is a hallmark of Alzheimer's disease, and alpha-synuclein is another similar protein to Parkinson's disease. In both cases, microglia exposed to CD22 blocking antibodies outperformed the hippocampus on the other side of the brain in the uptake of neurodegenerative related substances.

They then extended the exposure to one month, during which they continued to provide CD22 blocking antibodies to the brain. The researchers found that mice receiving these infusions performed better than control mice of the same age in two different learning and memory tests, which were commonly used to assess cognitive performance in mice. This also means that mice become smarter.

Blocking CD22 on mouse microglia restores their cognitive function to younger decimal levels, so CD22 can be used as a new target for the treatment of degenerative diseases.