Perturbing the LXR/SREBP axis to decipher protective and pathogenic AD/ADRD microglial phenotypes
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Microglia play both protective and pathogenic roles in neurodegenerative disease but mechanisms that specify or restrict these opposing activities remain poorly understood. Molecular, cellular, and genetic studies implicate defects in phagocytosis, lysosomal function and lipid metabolism as contributing to pathological phenotypes. In line with these findings, the accumulation of lipid droplets is a hallmark of microglia in aging and neurodegenerative disease states. Due to the essential roles of LXRs and SREBPs in the regulation of cellular cholesterol and fatty acid metabolism, we hypothesize that the formation of lipid droplets is a manifestation of general defects in the normal homeostatic functions of LXRs and SREBPs that are broadly linked to pathological microglia phenotypes. Although conventional LXR ligands have been shown to exert protective effects in mouse models of neurodegeneration, their mechanisms of action have not been established and they cannot be used clinically because they induce hypertriglyceridemia. Here, we will build on our prior work demonstrating that the endogenous LXR agonist desmosterol and synthetic desmosterol mimetics mimic normal physiology by coordinately regulating LXR and SREBP and do not induce hypertriglyceridemia. Three Specific Aims are proposed. In Specific Aim 1, we will test the hypothesis that age and inflammation-dependent formation of lipid droplets is regulated by the LXR and SREBP pathways by selectively knocking out LXRs or SREBPs in microglia and pharmacologically by treating animals with either the conventional LXR agonist GW3965 that selectively activates LXRs or the desmosterol mimetics that simultaneously activate LXRs and suppress SREBPs. In Specific Aim 2, we will test the hypothesis that coordinate regulation of LXRs and SREBPs in the brain by desmosterol mimetics reduce the number and/or activity of pathogenic microglia and confer similar or greater protection against neurodegeneration in the Tau/APOE4 model than the conventional LXR agonist GW3965 without causing hypertriglyceridemia. In Specific Aim 3 we will test the hypothesis that LXR and SREBP have conserved roles in regulating lipid metabolism in human iPSC-derived microglia in vitro and following engraftment into the brains of immune-deficient humanized mice. Effects of GW3965 and desmosterol mimetics will be assessed in vitro and in engrafted hosts under homeostatic conditions during aging and in response to LPS activation. In each Aim, we will investigate the molecular functions of LXRs and SREBPs by determining the effects of GW3965 and desmosterol mimetics on microglia transcriptomes and epigenetic landscapes and the genome wide binding patterns of LXRs and SREBPs. Collectively, these studies will advance understanding of the linkage of lipid droplets with neurodegeneration, provide insights into mechanisms underlying protective effects of LXR agonists, and potentially open a path towards clinical development of safe and effective LXR agonists for prevention and treatment of neurodegenerative disease.
