Nerve cells affected by Alzheimer's disease, illustration

Researchers at the Icahn School of Medicine at Mount Sinai have identified two proteins that affect the functioning of immune cells called macrophages in lipid-rich tissue, a finding that deepens the understanding of Alzheimer’s disease (AD) and could provide new targets for the treatment of AD and other diseases. The study, published Thursday in Nature Communications, provides new insight into the understanding of the role immune cell regulation plays in disease progression.

The research began to better understand the genes controlling macrophages—also called microglia when they are in the brain—to see how they respond to damage of fatty tissues such as those found in the brain. Current thinking is that macrophages/microglia are protective since they participate in the removing lipid-rich waste produced by tissue damage. The intent was to better understand the factors that help promote the waste removal activities of these cells.

In their study, the investigators identified two genes that are influential in this process— BHLHE40 and BHLHE41. Using CRISPR/Cas9 gene editing, the team deactivated these genes in lab-grown cells and then transformed them into microglia. The microglia with BHLHE40 and BHLHE41 edited out resembled the microglia that are associated with those seen in AD, showing an improved ability to remove cholesterol-rich waste.

“Through our analysis of single-cell datasets from multiple organs, we’ve uncovered pivotal regulators of immune cell function essential for tissue health,” said senior study author Alison M. Goate, DPhil, chair of Genetics and Genomic Sciences at Icahn Mount Sinai. “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.”

Building on this finding, the team is now researching whether microglia without BHLHE40 and BHLHE41 have the ability to clear amyloid proteins, which are key drivers of neurodegeneration and AD. For one experiment, the investigators will grow neurons and astrocytes in the lab that have known harmful AD mutations and then test what influence BHLHE40 and BHLHE41 have on beta-amyloid levels, neurodegeneration, and cytokine response. For the second experiment, researchers will inject the immune cells with and without BHLHE40 and BHLHE41 into AD mouse models to observe what effects the immune cell response may have on the development of Alzheimer’s-like plaques.

“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 such as neurons and astrocytes,” said Goate.

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