Understanding the vital role of immune cells in lipid-rich tissues, such as the brain, is important for advancing target therapies for Alzheimer's and related diseases. 

In a study published in Nature Communications, Icahn Mount Sinai researchers investigated the behavior of macrophage-controlling genes, known as microglia when within the brain, in response to damage in fatty tissues.

They uncovered two influential genes, BHLHE40 and BHLHE41, which they deactivated in cultured cells using the CRISPR-Cas9 gene editing technology. These modified cells were then transformed into microglia lacking BHLHE40 and BHLHE41, similar to the disease-associated microglia observed in Alzheimer's patients. These altered microglia remarkably enhanced their capability to clear cholesterol-rich waste.

Alison M. Goate, the senior study author and the Icahn Mount Sinai Chair of Genetics and Genomic Sciences, said their analysis of single-cell datasets across multiple organs allowed the team to identify the crucial regulators of immune cell function necessary for tissue health. 

"Our use of advanced models has further validated the critical role played by transcription factors BHLHE40 and BHLHE41, proteins that regulate gene expression by binding to specific DNA sequences, in controlling immune cell responses, presenting potential targets for therapeutic intervention," she said.

After identifying the role of BHLHE40 and BHLHE41, the team plans to conduct two experiments to explore microglia's effects without these influential genes on harmful amyloid proteins.

"We want to see how these cells, particularly those without the two genes, impact Alzheimer's-related phenotypes in both dish and mouse models. We predict that in mice, microglia without BHLHE40 and 41 will clear away beta-amyloid plaques more effectively than control microglia that have normal levels of BHLHE40 and 41. Also, we're exploring how lack of these genes in the brain immune cells affect other types of cells in the brain," added Dr. Goate.

Read the full article here to learn more about the study and insights into the team's future experiments.

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