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, Gary E. Landreth

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6532-6543
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number16
DOIs
StatePublished - Apr 22 2015
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Microglia
  • Nuclear receptors
  • Phagocytosis

ASJC Scopus subject areas

  • Neuroscience(all)

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    Savage, J. C., Jay, T., Goduni, E., Quigley, C., Mariani, M. M., Malm, T., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2015). Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. Journal of Neuroscience, 35(16), 6532-6543. https://doi.org/10.1523/JNEUROSCI.4586-14.2015