Can novel methods of analyzing how genes are activated in cells identify genetic mechanisms underlying Alzheimer’s?
David Gate, Ph.D.
Northwestern University Feinberg School of Medicine
Chicago, IL - United States
Genes play complex roles in late-onset Alzheimer’s disease (LOAD), the most common form of the disorder. One gene variation called APOE-e4, which provides instructions for making ApoE protein, is thought to promote LOAD in some populations. However, there are numerous other gene variations that likely impact Alzheimer’s risk, many of which have not been identified. To better understand the role of genes in Alzheimer’s, many scientists are studying how gene expression (or the conversion of genes into proteins) is affected in the disease. Gene expression takes place after the gene is turned “on” and a molecule called ribonucleic acid (RNA) is produced.
In initial studies, Dr. David M. Gate and colleagues analyzed the transcriptome (the complete set of genes turned “on” at a specific time) of different cell types in brain samples from individuals with and without Alzheimer’s. These individuals had participated in one of two studies of aging, and were part of a group known as the ROSMAP cohort. The researchers found that a specific type of microglia (immune cell of the brain) showed the most transcriptomic differences between the two brain sample groups. The microglia contained a receptor (or “docking site”) on the surface of the cell called Macrophage Scavenger Receptor 1 (MSR1). MSR1 is known to help immune cells take up and remove beta-amyloid, a protein that accumulates into hallmark plaques in Alzheimer’s. This finding suggests that “MSR1+ microglia” may prove an important target cell in the search for Alzheimer’s-related gene variations.
The researchers also explored two other methods for analyzing transcriptomes and genes in the brain. One technique can measure all transcriptomic and genetic changes in a specific section of brain tissue. This “spatial transcriptomic” method enabled Dr. Gate’s team to study how such changes impact the way cells interact with each other and with Alzheimer’s-related processes such as beta-amyloid clumping.
Dr. Gate and team will now conduct several experiments to verify and expand on their earlier results. First, they will use their spatial transcriptomic method on a second group of brain samples, in order to confirm their work with the ROSMAP cohort. They will analyze how changes in the transcriptomes of MSR1+ microglia may impact the way these cells interact with other brain cells and promote Alzheimer’s-related brain changes. Next, using ROSMAP brain samples, the researchers will study how certain changes that cells make to RNA over time (known as “RNA editing”) may be linked to Alzheimer’s. Specifically, the researchers will look for RNA editing changes that may lead to dementia-related changes in gene expression. Lastly, Dr. Gate and team will assess how transcriptomic and RNA editing changes may impact cognitive decline in people with Alzheimer’s. For this last effort, they will use cognitive data acquired over time from individuals in the ROSMAP cohort.
The results of this project could refine our understanding of how changes in RNA activity and gene expression promote Alzheimer’s. Ultimately, they could lead to the discovery of novel dementia-related genes, as well as novel methods of diagnosing and treating Alzheimer’s.
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