This study specifically revealed that repeated alcohol intoxication is associated with changes in gene expression indicative of disease progression in the brains of mice that were genetically predisposed to AD. Demonstrating that when the animals were exposed to intoxicating amounts of alcohol repeatedly, they exhibited signs of cognitive decline two months sooner than they typically would have.
“Adding ethanol to an Alzheimer’s genetic background pushes Alzheimer’s forward by a few months or a few years,” said co-lead author Federico Manuel Giorgi, Ph.D., a professor of Computational Genomics at the University of Bologna.
“We started seeing cognitive impairments in the alcohol-treated mice approximately two months before they would normally develop these impairments,” says co-lead author Pietro Paolo Sanna, MD, a professor of Immunology and Microbiology at Scripps Research.
When compared to control mice carrying the 3 genes that make them susceptible to AD that were not exposed to alcohol, the exposed animals became progressively worse at learning and remembering spatial patterns. Gene expression of more than 100,000 individual cells from the animals were characterized and compared from exposed and control animals to determine what was happening to these cells during AUD.
Alcohol exposure was found to be associated with widespread changes in gene expression in the prefrontal cortex. Exposed mice specifically had higher expression of genes associated with inflammation, neuronal excitability, as well as neurodegeneration, and these changes occurred in neurons, astrocytes, microglia, endothelial cells, and other supporting cells.
“This is interesting because it used to be thought that neurons were the ones carrying out all the responses associated with Alzheimer’s disease, and only recently have these cell types been recognized as having a role in Alzheimer’s pathogenesis,” says Giorgi.
Further comparison of gene transcription profiles of exposed and control animals of different ages as well as different stages of AD with the same genetic history revealed that the gene transcription profiles of the exposed mice resembled those of older mice with more severe cognitive decline than mice of their own age.
“When we compared the alcohol-exposed mice to the same type of mice with early or late progression of the disease—so mice that are not yet impaired in any way and mice that are really compromised—we found that the effect of alcohol is to move gene expression towards the advanced disease,” said Sanna.
“The mechanisms of progression that this dataset will uncover may apply to Alzheimer’s in general, even without alcohol,” says Sanna. “Ultimately, this gene expression analysis will identify key regulatory genes that drive Alzheimer’s progression.”
