Study Points to Novel Role for Microglia in Down Syndrome

Down syndrome is caused by an extra copy of part or all of human chromosome 21, and is the most commonly occurring chromosomal condition in the US. Children with Down syndrome often experience cognitive delays compared to typically developing children, although there’s substantial variation and the effects are usually mild or moderate. People with the syndrome also have a higher risk of certain medical conditions, including Alzheimer’s disease.

A number of studies have identified elevated levels of inflammation in people with Down syndrome, while separate research has also connected inflammation to cognitive delay or decline in people and research animals. In their study, neuroscientists Laura Cancedda, Laura Perlini, Giovanni Morelli, and Bruno Pinto of the Italian Institute of Technology in Genoa and colleagues set out to investigate a role for microglia—which, when in a so-called activated state, release cytokines known to promote neuroinflammation.

The team focused first on a mouse model of the condition, in which part of chromosome 16—the murine equivalent of human chromosome 21—is triplicated. These so-called Dp(16) mice show some of the traits seen in people with Down syndrome, including delayed development and difficulties with motor and cognitive skills, but not the dysfunctional neurogenesis or other abnormalities in brain development characteristic of some other mouse models of the condition and people with Down syndrome.

Comparing the brains of juvenile Dp(16) mice with those of control animals, the researchers didn’t find any differences in the overall numbers of microglia. However, Dp(16) mice had higher numbers of microglia in an activated state—they showed cell morphology, electrophysiology, and protein expression patterns associated with neuroinflammation.

The fact that they’re getting the same signatures in their young mice and they’re seeing something similar in younger human brains, I thought was really convincing.

—Elizabeth Head, University of California, Irvine

The researchers next knocked out some of these activated microglia in the brains of Dp(16) mice—either by feeding animals a drug that reduces the overall number of microglia, or by injecting the animals with acetaminophen, an anti-inflammatory drug that helps inhibit microglial activation, once a day for three days. Both sets of treated mice performed better on lab measures of cognition—such as discrimination between familiar and unfamiliar objects—than Dp(16) mice that hadn’t been treated. Testing acetaminophen on a different mouse model of Down syndrome produced similar results.

The effect of acetaminophen wore off relatively quickly, Morelli notes: mice tested a couple weeks after their last injection showed microglial morphology and cognitive performance similar to that of untreated mice. Additional experiments showed that the drug didn’t have a significant effect in adult animals, suggesting that microglial activation is particularly relevant during earlier stages of brain development, Cancedda adds.

To connect their findings to humans, the researchers examined the hippocampi of postmortem brains from people with Down syndrome who died before they reached 40. An analysis of gene and protein expression patterns and cell morphology revealed the same tell-tale signs of microglia activation that the team had found in mice.

Tarik Haydar, a neuroscientist at Children’s National Hospital in Washington, DC, who was not involved in the work, says that he was impressed by the study’s thoroughness. How microglia influence the developing brain, particularly as it relates to Down syndrome, has been largely unknown, he adds. The study authors “not only asked that question, they answered it quite comprehensively.”

Both Haydar and Head praise the team’s use of two separate mouse models and inclusion of postmortem human brain tissue, noting that similar findings across all three provide good evidence for microglial cells’ relevance in Down syndrome. “The fact that they’re getting the same signatures in their young mice and they’re seeing something similar in younger human brains, I thought was really convincing,” says Head.

In an email to The Scientist, Victoria Puig, a neuroscientist at the Hospital del Mar Medical Research Institute in Barcelona, calls the study a “tour de force” and praises its use of multiple techniques. She adds that while the findings provide evidence “that abnormal microglia may be a possible cause” of cognitive delays, Down syndrome “is a complex syndrome that combines alterations not only in the brain immune system but also in other systems,” including the cardiovascular system and wider patterns of gene expression. “Chronic treatment with anti-inflammatory drugs may not be sufficient” to treat cognitive problems in people, she writes, although it’s worth scientists investigating to see if it could help.

Cancedda says that researchers will need to learn more about how and over what timescale acetaminophen, a widely available and relatively safe drug, acts to reduce cognitive problems in the juvenile mice they studied, with an eye to possible clinical trials in the future. She cautions that there’s still a lot left to understand about acetaminophen’s effects on cognition and that people should not experiment with taking the drug outside a clinical setting.

Head agrees that the findings provide good justification for studies in humans, but should be interpreted with caution until carefully controlled trials have provided more information—not least because of potentially harmful side-effects or interactions between acetaminophen and other medications.

“The proper way to do this, just as the authors suggest, is to do a controlled clinical trial,” says Head. “I would love to see a clinical trial do that.”

B. Pinto et al., “Rescuing over-activated microglia restores cognitive performance in juvenile animals of the Dp(16) mouse model of Down syndrome,” Neuron, doi:10.1016/j.neuron.2020.09.010, 2020.

Clarification (October 7): The fourth paragraph of this article has been updated to add the name of study coauthor Laura Perlini.