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On April 3, a study published in the journal Nature, scientists from Stanford University found that blocking the activity of protein CD22 with an antibody can improve cognitive behavior in aging mice. Dr. Tony Wyss-Coray, a professor of neuroscience, led the research.

Dr. Wyss-Coray has been working for years to study what causes the brain to lose its sensitivity as it ages. A brain cell called microglia is one of his key research directions. These cells are both immune cells of the brain and “garbage-cleaning cells”, which are responsible for cleaning up cell debris and protein deposits accumulated by normal metabolic activities in the central nervous system.

 

On average, microglia’s garbage collection capacity declines in aging brains. The reason why this happens and the extent to which this decline in capacity has led to age-related cognitive losses is unclear. But it is certain that microglia “poor performance” plays a role in neurodegenerative diseases.

 

In AD and other neurodegenerative diseases (such as Parkinson’s disease, amyotrophic lateral sclerosis), the activation pattern of microglia genes is abnormal. High-risk mutations Many genes associated with AD are only active in microglia in the brain.

 

The procedure by which microglia are used to absorb and then ingest (thing-then-digest) waste is called phagocytosis. In this new study, the team led by Dr. Wyss-Coray hopes to identify genes that impair or enhance microphage phagocytosis using CRISPR/Cas9 knockout screening and RNA sequencing. The activity levels of these genes vary with age. Growth either increases significantly or decreases significantly.

 

In one of the experiments, the researchers selected about 3,000 genes encoding proteins. The standard is that they believe these proteins may become drug targets or have been used in drug discovery. They in turn blocked the ability of each gene to encode a protein in order to understand the effect of each block on the ability of mouse microglia to absorb fluorescently labeled latex particles (the brighter the light emitted by microglia, the ability to clean up the trash) The stronger it is).

 

In another parallel experiment, Dr. Wyss-Coray et al investigated which genes are more active in microglia in the hippocampus (the brain structure essential for learning and memory) in young and aging mice. Not active.

 

Surprisingly, when scientists compared the results of these two experiments, they found that only one gene called CD22 affected the phagocytosis of microglia. The activity of this gene in microglia increased significantly with age. Compared with young microglia, senescent microglia produce more CD22 copies (which means an increase in CD22 protein production); knocking out the gene greatly improves the phagocytosis of microglia.

 

Based on this discovery, Dr. Wyss-Coray and others began to focus on CD22. This gene is expressed in both mice and humans.

 

Subsequent experiments confirmed that the expression of CD22 protein (a B cell receptor) on the surface of microglia in aged mice was three times that of young mouse microglia. The use of antibody molecules can block the expression of CD22.

 

Specifically, in the study, scientists injected CD22 blocking antibodies into the hippocampus on one side of the mouse brain and injected similar antibodies that failed to bind to CD22 in the hippocampus on the other side.

 

In addition to these antibodies, they also used fluorescently labeled myelin fragments. Myelin covers many nerve cells and provides insulation; however, many myelin fragments accumulate in the aging brain, inhibiting the ability of microglia to clear them.

Dr. Wyss-Coray’s team found that after 48 hours, the myelin fragments they injected into the hippocampus of mice “on the side that injected the CD22 blocking antibody” were far less common than the “on the side injected with the pseudo-antibody”.

 

Next, the scientists performed a similar experiment, replacing the myelin fragment with β-amyloid, a feature of AD, and α-synuclein, which is associated with Parkinson’s disease. In both cases, microglia treated with CD22 blocking antibodies are superior to untreated microglia on the other side of the brain in absorbing these substances associated with neurodegenerative diseases.

 

Later, the researchers extended the exposure time from 48 hours to 1 month. They improved the injection technique to provide continuous CD22 blocking antibody injections on both sides of the brain. The results showed that, consistent with their previous findings, older mice that received CD22 blocking antibody injections were smaller than the control group of the same age in two learning and memory tests commonly used to assess cognitive performance in mice. it is good.

 

“CD22 blocking antibody treatment has made older mice smarter. Blocking CD22 in microglia repairs their cognitive function and restores it to the level of young mice,” Dr. Wyss-Coray said.

 

In summary, the study found a new way to get dysfunctional microglia back to a young state. Scientists believe that CD22 is a new target for the treatment of neurodegenerative diseases.

 

In recent years, in the case of repeated failures in the development of targeted β-amyloid drugs, regulation of microglia has become a new idea for the treatment of AD.

 

A paper published in Cell in 2017 found that high-risk mutations in the TREM2 gene cause microglia energy deficits that prevent them from protecting neurons from harmful plaques. Later studies have shown that up-regulation of TREM2 signaling can prevent disease progression and even restore cognitive function in AD mice. Currently, an antibody drug (AL002) targeting TREM2 has entered Phase I clinical practice.

 

In addition to regulating microglia, reducing inflammation in the brain is also an AD treatment strategy that some teams are trying. Inflammation is usually a “good thing”, for example, it can clear the infection and help heal the wound. But in patients with AD, inflammation is somehow confusing, becoming too strong, lasting too long, destroying neurons.

 

Dr. Linda Van Eldik of the University of Kentucky and her partners are looking for a drug that blocks “bad inflammation” in the brain. Recently, they are preparing to test a drug called MW-151 in humans. It is hoped that these methods of bypassing β-amyloid will surprise AD treatment.

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