Alcohol alters gene expression in microglial cells and the immune system, impairing the ability of phagocytes to clear amyloid β (Aβ) plaque, in findings that may explain the link between alcohol consumption and the risk for Alzheimer‘s disease (AD).
As seen in a lot of research involving alcohol exposure, the amount matters. “Our results demonstrate that microglial phagocytosis of Aβ1-42 [the 42–amino acid version of amyloid β] is significantly suppressed following one-day exposure to 75 mM ethanol,” the researchers, with principal investigator Douglas L. Feinstein, from the Department of Anesthesiology at the University of Illinois at Chicago and the Department of Veterans Affairs, Jesse Brown VA Medical Center, Illinois, write.
“This dose of ethanol is in the high range and is attained in humans following binge drinking or in heavy drinkers,” they add.
In the current study, alcohol appears to be doing something unique. “We activated cells with alcohol alone or with a strong inflammatory combination. The two responses were very different,” Feinstein told Medscape Medical News. “Alcohol is causing some type of activation in microglial cells, and it’s different from typical inflammation.”
Growing Interest in Neuroinflammation
The investigators exposed rat microglial cells to alcohol or to a mixture of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interferon-γ. They next compared genetic activation at 24 hours. Results revealed 312 messenger RNAs (mRNAs) expressed differently after alcohol exposure.
One of the strongest changes associated with alcohol exposure involved phagocyte pathways, supporting the concept that high alcohol exposure could thwart the body’s ability to remove Aβ through the normal phagocytosis process.
“While changes in inflammatory mRNAs were expected, observations that alcohol induces changes in mRNAs involved in phagocytosis including members of the [immune] complement system is a novel finding suggesting that alcohol consumption can lead to dysregulation of clearance processes in the CNS [central nervous system],” the authors write.
Feinstein did not have a specific message for neurologists or other physicians treating people with AD at this point, “other than to inquire if patients are consuming large quantities of alcohol, and to advise them to cut back.”
Traditionally, experts saw AD primarily as a neurodegenerative disease of the elderly with extracellular accumulation of misfolded Aβ peptide and intracellular neurofibrillary tangles. Only recently has neuroinflammation emerged as an important component of Alzheimer‘s pathology, experts pointed out in a review article (Nat Immunol. 2015;16:229-236).
“Experimental, genetic and epidemiological data now indicate a crucial role for activation of the innate immune system as a disease-promoting factor. The sustained formation and deposition of Aβ aggregates causes chronic activation of the immune system and disturbance of microglial clearance functions.”
In addition, microglial activation appears increasingly associated with the chronic alcohol exposure and withdrawal neuorinflammation (Int Rev Neurobiol. 2014;118:13-39). Other research shows that the genes implicated in neuroinflammatory processes observed with alcohol are expressed in the microglia (Neuropharmacology. 2017;122:56-73).
For the study, the investigators quantified the amount of Aβ internalized through microglial phagocytosis. The average amount decreased by 16% over 45 minutes when cells were exposed to alcohol and by 37% when they were exposed to the cytokine combination.
As an indirect measure of microglial neuroinflammation, the researchers measured nitrite levels in the culture media. Alcohol increased these levels by twofold above media-only controls. Upon exposure to the proinflammatory cytokines, nitrite levels increased threefold.
On a positive side note, available medication, such as minocycline and tigecycline, have been shown to reduce microglial activation.
“Maybe we should consider using these drugs to decrease or avoid” these physiologic processes, Feinstein said.
Use of primary rat microglia, which differ in gene expression and function from isolated brain microglia, is a limitation. In addition, the researchers assessed only a single, short-term exposure to ethanol, meaning the results may not be generalizable to long-term alcohol exposure.
These new findings add to the literature by characterizing specifics about the microglial genetic transcriptome after alcohol treatment or consumption.
Feinstein added that his team has a research grant under review at the National Institutes of Health and aim to further evaluate the effects of alcohol on the microglial transcriptome.
Commenting on the findings for Medscape Medical News, Victor W. Henderson, MD, professor of health research & policy (epidemiology) and of neurology & neurological sciences at Stanford University, California, noted that “recent observations raise the possibility that moderate alcohol consumption may increase dementia risk.”
The research by Feinstein and colleagues does not address this issue directly. Instead, these investigators studied rat microglia, brain cells involved in immune defense, and inflammation
“They show that alcohol might reduce the ability of microglia to remove amyloid from the brain. This finding is interesting because the build-up of amyloid is likely an early step in the development of Alzheimer‘s disease,” added Henderson, who is also director of the Stanford Alzheimer‘s Disease Research Center and a fellow of the American Academy of Neurology. “We do not know, however, whether these laboratory results will prove relevant to human disease.”
A National Institutes of Health grant and a Research Career Scientist Award from the Department of Veteran Affairs funded the study. Feinstein and Henderson have disclosed no relevant financial relationships.
J Neuroinflamm. Published online May 14, 2018. Abstract