Using novel genetic and genomic tools, researchers at the Icahn School of Medicine at Mount Sinai have shed light on the role of immune cells called macrophages in lipid-rich tissues like the brain, advancing our understanding of Alzheimer’s and other diseases.
The study, published in the March 6 online issue of Nature Communications, represents a step forward in understanding immune cell regulation and its impact on disease progression.
The researchers initially studied genes controlling macrophages, also referred to as microglia when they are in the brain, particularly in response to damage of fatty tissues like the brain. Disease-associated microglia/macrophages are thought to be protective, as they participate in removing lipid-rich waste derived from tissue damage. Therefore, researchers wanted to find factors that promote the “garbage removal” activity of these cells.
They identified two influential genes, BHLHE40 and BHLHE41, and used advanced gene editing technology (CRISPR-Cas9) to deactivate them in lab-grown cells. These cells were then transformed into microglia. The resulting microglia lacking BHLHE40 and BHLHE41 resembled disease-associated microglia observed in Alzheimer’s disease, showing improved ability to clear cholesterol-rich waste. Confirmation came from experiments on cultured human peripheral macrophages.
