BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer’s disease and other disorders of lipid-rich tissues

Anna Podleśny-Drabiniok, Gloriia Novikova, Yiyuan Liu, Josefine Dunst, Rose Temizer, Chiara Giannarelli, Samuele Marro, Taras Kreslavsky, Edoardo Marcora () and Alison Mary Goate ()
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Anna Podleśny-Drabiniok: Icahn School of Medicine at Mount Sinai
Gloriia Novikova: Icahn School of Medicine at Mount Sinai
Yiyuan Liu: Icahn School of Medicine at Mount Sinai
Josefine Dunst: Karolinska University Hospital
Rose Temizer: Icahn School of Medicine at Mount Sinai
Chiara Giannarelli: NYU Cardiovascular Research Center, New York University School of Medicine
Samuele Marro: Icahn School of Medicine at Mount Sinai
Taras Kreslavsky: Karolinska University Hospital
Edoardo Marcora: Icahn School of Medicine at Mount Sinai
Alison Mary Goate: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Genetic and experimental evidence suggests that Alzheimer’s disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, sc/nRNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as DLAMs. Using macrophage sc/nRNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40/41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.

Date: 2024
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DOI: 10.1038/s41467-024-46315-7

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