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Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease
Journal article   Open access   Peer reviewed

Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease

Julie C Savage, Taylor Jay, Elanda Goduni, Caitlin Quigley, Monica M Mariani, Tarja Malm, Richard M Ransohoff, Bruce T Lamb and Gary E Landreth
The Journal of neuroscience, Vol.35(16), pp.6532-6543
04/22/2015
DOI: 10.1523/JNEUROSCI.4586-14.2015
PMCID: PMC4405560
PMID: 25904803
url
https://doi.org/10.1523/JNEUROSCI.4586-14.2015View
Published (Version of record) Open Access

Abstract

Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequent deposition of amyloid (Aβ) within the brain. The brain's immune cells migrate to and invest their processes within Aβ plaques but are unable to efficiently phagocytose and clear plaques from the brain. Previous studies have shown that treatment of myeloid cells with nuclear receptor agonists increases expression of phagocytosis-related genes. In this study, we elucidate a novel mechanism by which nuclear receptors act to enhance phagocytosis in the AD brain. Treatment of murine models of AD with agonists of the nuclear receptors PPARγ, PPARδ, LXR, and RXR stimulated microglial phagocytosis in vitro and rapidly induced the expression of the phagocytic receptors Axl and MerTK. In murine models of AD, we found that plaque-associated macrophages expressed Axl and MerTK and treatment of the cells with an RXR agonist further induced their expression, coincident with the rapid reduction in plaque burden. Further characterization of MerTK(+)/Axl(+) macrophages revealed that they also expressed the phagocytic receptor TREM2 and high levels of CD45, consistent with a peripheral origin of these cells. Importantly, in an ex vivo slice assay, nuclear receptor agonist treatment reversed the AD-related suppression of phagocytosis through a MerTK-dependent mechanism. Thus, nuclear receptor agonists increase MerTK and Axl expression on plaque-associated immune cells, consequently licensing their phagocytic activity and promoting plaque clearance.
 Alzheimer Disease - metabolism Alzheimer Disease - pathology Animals Benzoates - pharmacology Benzylamines - pharmacology Bexarotene c-Mer Tyrosine Kinase Cells, Cultured Disease Models, Animal Gene Expression Regulation - drug effects Gene Expression Regulation - physiology Leukocyte Common Antigens - metabolism Macrophages - drug effects Macrophages - metabolism Male Membrane Glycoproteins - metabolism Mice Microglia - drug effects Microglia - metabolism Myeloid Cells - drug effects Myeloid Cells - metabolism Phagocytosis - drug effects Phagocytosis - physiology Pioglitazone Plaque, Amyloid - metabolism Proto-Oncogene Proteins - biosynthesis Receptor Protein-Tyrosine Kinases - biosynthesis Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - metabolism Receptors, Immunologic - metabolism Tetrahydronaphthalenes - pharmacology Thiazoles - pharmacology Thiazolidinediones - pharmacology

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