Combating Alzheimer's by restoring the brain's clean-up crew

In the central nervous system, microglia are responsible for scouting around for debris such as damaged neurons and protein plaques, and then cleaning it up in a process known as phagocytosis. As the brain ages, that garbage-engulfing function seems to diminish. But figuring out what molecular changes are causing the impairment—and whether that has to do with cognitive losses—has been challenging.

Now, using CRISPR-Cas9 knockout screens and RNA sequencing, a Stanford University team of scientists has identified CD22—a B-cell receptor that keeps immune responses in check—as a negative controller of microglial phagocytosis. Tuning down CD22 appears to improve cognitive function in aged mice.

The researchers reported their findings in a study in Nature. They believe the insight could open up new therapeutic approaches to treating or preventing neurodegenerative diseases.

The researchers first hypothesized that microglia could play a role in neurodegeneration due to their scavenger function; after all, toxic accumulation of proteins like beta amyloid and alpha synuclein are hallmarks of Alzheimer’s disease and Parkinson’s disease, respectively.

"Many of the genes whose high-risk variants have recently been linked to Alzheimer's disease are known to be active in the brain only in microglia," Tony Wyss-Coray, the study’s senior author, said in a statement.

Wyss-Coray and colleagues screened nearly 3,000 genes that are currently targetable with drugs for clues as to which ones might contribute to age-related decline in microglial phagocytosis. They blocked each gene one by one to see its effects on mouse microglia’s ability to ingest fluorescently labeled latex. At the same time, the researchers studied the mouse brain's hippocampus, which is essential to learning and memory, to determine what genetic changes are happening in young and old animals.

Both experiments pointed to a single target: CD22. Older microglia produced more copies of the gene than younger ones did, and knocking CD22 out promoted microglial phagocytosis, the researchers found.

To further verify their findings, the scientists injected a CD22-blocking antibody or a control antibody into opposite brain hemispheres of the same aged mouse. Meanwhile, they co-administered fluorescent myelin debris. Myelin is the protecting sheath around nerves. Myelin debris can accumulate in aging brains and has been known to overwhelm microglia, according to the researchers.

After two days, the brain region that had been treated with the anti-CD22 antibody showed significantly more clearance of myelin debris than did the other side, the team reported. Similar results were observed after the investigators replaced myelin with beta amyloid and alpha synuclein.

The role of microglia in the central nervous system's immune response has been a popular target in neurological studies. Scientists at the University of Florida recently found that soluble versions of toll-like receptors, which reside in microglia and contribute to the neuro-inflammatory response seen in Alzheimer’s, could increase uptake of amyloid plaques into microglia without triggering inflammation. In another study, scientists at the University of Cambridge found that reprogrammed skin stem cells—which can develop into nerve cells—could reduce the levels of succinate, which in turn could dampen microglia’s immune attack on myelin in multiple sclerosis.

In the Stanford study, Wyss-Coray's team continuously infused CD22 antibodies on both sides of mice’s brains. After a month, the CD22-inhibited old mice exhibited improved spatial memory and associative memory in two tests versus the control mice.

"CD22 is a new target we think can be exploited for treatment of neurodegenerative diseases," Wyss-Coray said.

Moving forward, the researchers hope to investigate the causes of CD22 over-expression in the aging brain. They said in the study that "[d]etermining whether CD22 function in the CNS is conserved between mice and humans will be an important step before translational studies are initiated."

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