Knowing the characteristics that distinguish the brain of people suffering from Alzheimer’s from that of cognitively healthy people is key to better understanding this type of dementia and being able to prevent and treat it successfully. Scientists at the University of Washington School of Medicine (UW Medicine) have now found that immune cells in the brains of people with Alzheimer’s disease appear to behave differently than those of individuals who had healthy brains for their age, as revealed by an analysis of the genetic activity of the cells.
This finding suggests that it might be possible to treat Alzheimer’s disease by altering the behavior of these cells, said Katherine Prater, an expert in neuroinflammation and interim instructor of neurology at the University of Washington School of Medicine. “If we can determine what they are doing, we could change their behavior with treatments that could prevent or delay this disease,” she said. The results of the work have been published in Nature Aging.
Prater and colleagues from UW Medicine, the Fred Hutchinson Cancer Center, Arizona State University, and the University of North Carolina at Chapel Hill looked at immune cells called microglia, which play important roles in the brain but are not well understood for their role in Alzheimer’s disease. . For example, they seem to protect the brain by eliminating amyloid deposits – the accumulations of toxic proteins that form in the brains of those affected by this dementia – but they may also contribute to an inflammatory process observed in Alzheimer’s that leads to death. of the brain cells.
Alter the activity of cells that contribute to Alzheimer’s
To better understand the activity of these cells, the researchers examined which genes were active in microglia from the brains of people with Alzheimer’s and those who did not. Because genes control a cell’s behavior, knowing which ones are active can help reveal what a cell is probably doing.
“Now that we have determined the genetic profiles of these microglia we can try to identify ways to change behavior that may be contributing to Alzheimer’s disease.”
To identify which genes were active, the scientists took advantage of the fact that when a gene is activated, the instructions encoded in its DNA sequence are copied or transcribed into a related molecule called RNA. Therefore, by sequencing RNA in the nucleus of a cell using a technique called single-nucleus RNA sequencing, it is possible to know which genes are active in different cells.
In this way, they studied the microglia in the brain of 12 people who died with Alzheimer’s and 10 who did not suffer from this disease and discovered that the populations of microglia in both sets of brains were diverse, and that the populations were divided into 10 subpopulations, each one of which, based on gene activity, probably has different characteristics and behaviors.
Although the microglia populations were similar in both brains, the mix was different, with some populations being more prevalent in brains affected by Alzheimer’s disease. The differences could be attributed to the cells contributing to the destruction of brain cells seen with Alzheimer’s, or they could be due to the destruction caused by the disease, Prater said: “At this point, we can’t say whether the microglia are causing the pathology or if the pathology is causing these microglia to alter their behavior.
Among the populations that were most prevalent in brains affected by Alzheimer’s disease were cells that appear to be in a pre-inflammatory state. Those cells may have a diminished ability to perform the cleaning tasks that microglia normally do. There were also fewer protective cells that are believed to promote healthy aging.
“Now that we have determined the genetic profiles of these microglia, we can try to figure out exactly what they are doing and hopefully identify ways to change their behaviors that may be contributing to Alzheimer’s disease,” Prater concludes.
