A Cleveland Clinic research team studying alcohol and the brain discovered a new way that alcohol abuse can cause brain dysfunction and damage: through immune cells called microglia. The research also identified a potential new treatment target.
The team showed that in a brain affected by alcohol, microglia tear down the extracellular matrix (ECM), the scaffold that surrounds our neurons. The ECM physically holds our brain cells together and allows them to work properly. When it's disrupted, our neurons can't communicate as effectively. Severe ECM disruption can affect our ability to move, think and even remain alert.
The research, published in Immunity by Cell Press , is new, fundamental knowledge that already guides the research team to explore new ways to prevent alcohol-related brain damage, says senior author Dimitrios Davalos, PhD.
Microglia are the brain’s resident immune cells that monitor and respond to damage and abnormalities in our brains, often acting as vacuum cleaners sucking up and cleaning out debris. Microglia also prune neuronal connections as part of healthy brain development.
Each microglial cell is constantly surveying our brain with its many branch-like processes. Dr. Davalos's team used advanced imaging techniques to follow the same microglia over time, before and after repeated exposure to alcohol. They made several discoveries:
Dr. Davalos says that his team's findings could guide new treatments that prevent alcohol-associated brain damage by targeting the brain’s immune system instead of neurons.
“For years, alcohol’s effects on the brain were largely viewed through the lens of neurons, and for good reason: alcohol acts directly on neuronal receptors,” he explains. “By following microglia in real time, we were able to see that they aren’t simply responding to damage. They drive the detrimental changes alcohol causes in the brain. And if they drive the damage, they can be targeted with treatment.”
The team found a potential target in MyD88, a protein that switches microglia on when their sensors detect tissue injury or other danger signals, such as those triggered by alcohol. Deleting the MyD88 gene from microglia before alcohol exposure blocked their response to alcohol and protected the brain from ECM and neuronal damage, while also reducing sedation and associated impairments – even with equally high blood alcohol levels.
The implications of these discoveries could extend beyond alcohol, Dr. Davalos says.
"We discovered a specific neuroimmune route that alcohol activates, but it’s possible that other drugs can turn that pathway on as well," he says. "My lab is looking into how we can target microglia or protect the brain’s ECM to prevent or limit brain damage, from substance use and possibly even other neurological diseases."
Immunity
Microglia-mediated extracellular matrix disruption drives neuronal dysfunction, motor impairments, and sedation following alcohol abuse
8-Oct-2026