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

Background

Genetic and experimental evidence strongly implicates myeloid cells in the etiology of AD and suggests that AD-associated alleles and genes may modulate disease risk by altering the transcriptional and cellular responses of macrophages (like microglia) to damage of lipid-rich tissues (like the brain). Specifically, recent single-cell/nucleus RNA sequencing (sc/nRNA-seq) studies identified a transcriptionally distinct state of subsets of macrophages in aging or degenerating brains (usually referred to as disease-associated microglia or DAM) and in other diseased lipid-rich tissues (e.g., obese adipose tissue, fatty liver, and atherosclerotic plaques). We collectively refer to these subpopulations as lipid-associated macrophages or LAMs. Importantly, this particular activation state is characterized by increased expression of genes involved in the phagocytic clearance of lipid-rich cellular debris (efferocytosis), including several AD risk genes.

Methods

We used sc/nRNA-seq data from human and mouse microglia from healthy and diseased brains and macrophages from other lipid-rich tissues to reconstruct gene regulatory networks and identify transcriptional regulators whose regulons are enriched for LAM response genes (LAM TFs) across species. We then used gene knock-down/knock-out strategies to validate some of these LAM TFs in human THP-1 macrophages and iPSC-derived microglia

Results

We nominate 11 strong candidate LAM TFs shared across human and mouse networks (

Conclusions

Taken together, this study nominates transcriptional regulators of the LAM response, experimentally validates BHLHE40/41 in human and mouse macrophages/microglia, and provides novel targets for therapeutic modulation of macrophage/microglia function in AD and other disorders of lipid-rich tissues.

Déclaration de conflit d'intérêts

Competing interests A.M.G.: Scientific Advisory Board (SAB) Genentech; SAB Muna Therapeutics; S.M.: consultant Dorian Therapeutics, Turn Biotechnologies. C.G. is listed as an inventor on Tech 160808G PCT/US2022/017777 filed by the Icahn School of Medicine at Mount Sinai, which has no competing interest with this work. G.N. is an employee of Genentech, a member of the Roche group, and owns company stock. The remaining authors declare that they have no competing interests.