Immune molecule long tied to inflammation may benefit the aging brain

Inflammation in the brain is usually seen as harmful in the aging process—it’s thought to contribute to Alzheimer’s and dementia. But a new study in mice suggests that inflammation, led by an immune molecule called STING (stimulator of interferon genes), might have a role in protecting the aging brain. The findings also have implications for new experimental Alzheimer’s drugs that are designed to block STING.

For the study published in Cell Reports, scientists at Tufts University School of Medicine examined brain function, inflammation, and movement in mice genetically engineered to lack STING, compared with normal controls. They found that mice without STING had worse memory and movement problems, mimicking the senility and frailty seen in people with dementia and Alzheimer’s disease.

“Our data suggest that the inflammatory processes that STING supports may actually be necessary for the brain to stay healthy and in balance during old age,” says Shruti Sharma, an assistant professor of immunology at Tufts University School of Medicine and the study’s senior author.

The findings challenge long-held assumptions about the immune molecule. “Numerous studies have tied STING in different ways to inflammatory processes seen in illnesses, ranging from cancer to diabetes to autoimmune disorders,” says Sharma. “Since STING drives inflammation during infections and other health conditions, the field largely has accepted that it will contribute to age-related disease.”

But Sharma says previous studies did not account for the fact that more than 40 percent of people are born with variations of the STING gene that cause the molecule to be absent or not work well in the body. “As these people live their entire lives with a loss of STING functionality, their immune systems likely adapt to compensate for that loss somehow, yet the ‘how’ of this adaptation remains unexplored,” she says.

To understand the effects that such adaptive changes may have on the brain over time, Sharma and her team studied mice lacking STING versus control mice across their lifespans. Studying the animals as they naturally aged, the researchers discovered that the mice without STING developed signs of more damaging inflammation than that seen in normal aging brains. This was most strongly seen in changes to how critical immune cells called microglia acted in the brain.

“Microglia are primarily known to prune damaged neurons, clear the brain of debris, and support other brain cells to keep everything in balance,” says Sharma. “In the absence of STING, the efficacy of microglia in clearing debris dropped significantly. If they’re not doing a great job at clearing dying brain cells or age-related buildups of harmful proteins or fatty molecules, that is invariably going to accelerate age-related brain diseases.”

A key support function of microglia is to help maintain the blood-brain barrier, the specialized network of blood vessels and tissue in the brain that help protect it from harmful intruders like viruses and bacteria, while allowing oxygen and essential nutrients to pass through. Damage to the blood-brain barrier disrupts overall brain function, which often first shows up as problems with movement.

Given the movement problems noted in the mice without STING, the team looked to see if there were any signs of a compromised blood-brain barrier and associated bleeding in their brains. They found that the mice lacking STING indeed had leaky blood-brain barriers and increased deposits of blood caused by damaged blood vessels around the brain.

As the absence of STING leads to higher inflammatory burdens, the Sharma lab plans to investigate which other immune pathways are activated in the absence of STING. Identifying these pathways will help determine whether they deliver the same protective benefits as STING or if gene therapies to restore STING function might instead be safer and more effective.

Earlier, short-term studies in mice emphasized a negative role for STING in aging-related brain decline. These contributed to the rapid development of experimental drugs that block STING activity and are planned for use in treating Alzheimer’s disease. As this new study’s findings suggest that turning STING off may have unexpected detrimental effects on brain function and overall health, further research may be needed to help future drugs avoid unexpected side effects from turning STING off, especially in the many people whose STING function is already low.

Citation: Katherine Sulka, a postdoctoral researcher at Tufts University School of Medicine, carried out this work as a doctoral candidate in the Sharma lab and is the first author in this study. Research reported in this article was supported by the National Institutes of Health under award numbers R01AI142005, 1R56AG082812-01, R01HL144477, R01HL165725, S10OD03203, F31HL159907, F30HL162200, F31HL177963, and UM1TR004398, as well as through private research foundations. Complete information on authors, funders, methodology, limitations, and conflicts of interest is available in the published paper. 

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.