Alcohol use disorder triggers a distinct immune response linked to neurodegeneration

New research published in Brain, Behavior, and Immunity provides evidence that alcohol use disorder triggers a distinct type of immune response in the brain. The findings suggest that excessive alcohol consumption shifts the brain’s immune cells into a reactive state that ultimately damages neurons. The study identifies a specific cellular pathway linking alcohol exposure to neurodegeneration.

Scientists have recognized for some time that the brain possesses its own immune system. The primary component of this system is a type of cell known as microglia. Under normal conditions, microglia function as caretakers that maintain the health of the brain environment. They clear away debris and monitor for threats.

When the brain encounters injury or disease, microglia undergo a transformation. They become “reactive,” changing their shape and function to address the problem. While this reaction is intended to protect the brain, chronic activation can lead to inflammation and tissue damage.

Previous investigations established that heavy alcohol use increases inflammation in the brain. However, the specific characteristics of the microglia in individuals with alcohol use disorder remained poorly defined. It was unclear if these cells behaved similarly to how they react in other neurodegenerative conditions, such as Alzheimer’s disease.

The authors of the new study sought to create a detailed profile of these cells. They aimed to understand how reactive microglia might contribute to the brain damage and cognitive deficits often observed in severe alcohol dependency.

“We wanted to clearly define the microglial activated phenotype in alcohol use disorder using both morphology and protein expression from histochemistry and compare that to messenger RNA transcription changes,” said study author Fulton T. Crews, a John Andrews Distinguished Professor at the University of North Carolina at Chapel Hill.

The research team examined post-mortem brain tissue. They focused on the orbital frontal cortex, a region of the brain involved in decision-making and impulse control. The samples included tissue from twenty individuals diagnosed with alcohol use disorder and twenty moderate drinking controls. The researchers matched these groups by age to ensure that aging itself did not skew the results.

The researchers utilized two primary methods to analyze the tissue. First, they used immunohistochemistry to visualize proteins within the cells. This technique allows scientists to see the shape and quantity of specific cell types. Second, they employed real-time PCR to measure gene expression. This reveals which genetic instructions are being actively turned into proteins. By comparing protein levels and gene activity, the researchers could build a comprehensive picture of the cellular state.

The analysis revealed significant changes in the microglia of the alcohol use disorder group. These cells displayed a “reactive” phenotype characterized by increased levels of specific proteins. Markers associated with inflammation and cellular cleanup, such as Iba1 and CD68, were substantially elevated. The density of Iba1 staining, which indicates the presence and size of these cells, was more than ten times higher in the alcohol group compared to controls.

The researchers also identified a discrepancy between protein levels and gene expression. While the proteins for markers like Iba1 and CD68 were abundant, the corresponding mRNA levels were not significantly changed. This indicates that relying solely on gene expression data might miss key signs of immune activation in the brain. It suggests that the increase in these markers occurs at the protein level or through the accumulation of the cells themselves.

The researchers found that this microglial profile is distinct from what is typically seen in Alzheimer’s disease. In Alzheimer’s, reactive microglia often show increases in a receptor called TREM2 and various complement genes. The alcohol-exposed brains did not show these specific changes. Instead, they displayed a reduction in Tmem119, a marker associated with healthy, homeostatic microglia. This helps distinguish the pathology of alcohol use disorder from other neurodegenerative diseases.

Beyond microglia, the study investigated astrocytes. Astrocytes are another type of glial cell that generally support neuronal function. The data showed that markers for reactive astrocytes were higher in the alcohol group. This increase was strongly correlated with the presence of reactive microglia.

The researchers also assessed the health of neurons in the orbital frontal cortex. They observed a reduction in neuronal markers, such as NeuN and MAP2. This reduction indicates a loss of neurons or a decrease in their structural integrity. When the researchers analyzed the relationships between these variables, they found a clear pattern. The data supports a model where alcohol activates microglia, which in turn activates astrocytes. These reactive astrocytes then appear to contribute to neuronal damage.

To verify this sequence of events, the researchers turned to a mouse model. They exposed mice to chronic ethanol levels that mimic binge drinking. As expected, the mice developed reactive microglia and astrocytes, along with signs of oxidative stress. The team then used a genetic tool called DREADDs to selectively inhibit the microglia.

When the researchers prevented the microglia from becoming reactive, the downstream effects were blocked. The mice did not develop reactive astrocytes despite the alcohol exposure. Furthermore, the markers of oxidative stress and DNA damage were reduced. This experimental evidence provides strong support for the findings in human tissue. It suggests that microglia act as the primary driver of the neuroinflammatory cascade caused by alcohol.

“Neuroinflammation and activated microglia are linked to multiple brain diseases, including alcohol use disorder, but are poorly defined,” Crews told PsyPost. “They are likely not the same across brain disorders and we are trying to improve the definition. Studies finding activated microglia in Alzheimer’s have observed large increases in expression of complement genes, but our study did not find complement proteins increased in alcohol use disorder, suggesting different types of activation.”

The researchers also noted a connection between the severity of the cellular changes and drinking history. In the human samples, levels of reactive glial markers correlated with lifetime alcohol consumption. Individuals who had consumed more alcohol over their lives tended to have more extensive activation of these immune cells. This points to a cumulative effect of drinking on brain health.

Future research will likely focus on how these reactive microglia differ from those in other conditions. Understanding the unique “signature” of alcohol-induced inflammation could lead to better diagnostic tools.

Scientists may also explore whether treatments that target glial activation could protect the brain from alcohol-related damage. Developing therapies to block this specific immune response could potentially reduce neurodegeneration in individuals struggling with alcohol addiction.

“Our long term goal is to understand how microglia contribute to disease progression and to develop therapies blocking microglial activation and neuroinflammation that prevent chronic brain diseases,” Crews said.

The study, “Cortical reactive microglia activate astrocytes, increasing neurodegeneration in human alcohol use disorder,” was authored by Fulton T. Crews, Liya Qin, Leon Coleman, Elena Vidrascu, and Ryan Vetreno.