Apolipoprotein J (clusterin) activates rodent microglia in vivo and in vitro

Z. Xie, M. E. Harris-White, P. A. Wals, S. A. Frautschy, C. E. Finch, Todd E. Morgan*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Apolipoprotein J (apoJ; also known as clusterin and sulfated glycoprotein (SGP)-2) is associated with senile plaques in degenerating regions of Alzheimer's disease brains, where activated microglia are also prominent. We show a functional link between apoJ and activated microglia by demonstrating that exogenous apoJ activates rodent microglia in vivo and in vitro. Intracerebroventricular infusion of purified human plasma apoJ (∼4 μg over 28 days) activated parenchymal microglia to a phenotype characterized by enlarged cell bodies and processes (phosphotyrosine immunostaining). In vitro, primary rat microglia were also activated by apoJ, with changes in morphology and induction of major histocompatibility complex class II (MHCII) antigen. ApoJ increased the secretion of reactive nitrogen intermediates in a dose-dependent manner (EC50 112 nM), which was completely blocked by aminoguanidine (AG), a nitric oxide synthase inhibitor. However, AG did not block the increased secretion of tumor necrosis factor-α by apoJ (EC50 55 nM). Microglial activation by apoJ was also blocked by an anti-apoJ monoclonal antibody (G7), and by chemical cleavage of apoJ with 2-nitro-5- thiocyanobenzoate. The mitogen-activated protein kinase kinase and protein kinase C inhibitors PD98059 and H7 inhibited apoJ-mediated induction of reactive nitrogen intermediate secretion from cultured microglia. As a functional measure, apoJ-activated microglia secreted neurotoxic agents in a microglia-neuron co-culture model. We hypothesize that ApoJ contributes to chronic inflammation and neurotoxicity through direct effects on microglia.

Original languageEnglish (US)
Pages (from-to)1038-1046
Number of pages9
JournalJournal of neurochemistry
Volume93
Issue number4
DOIs
StatePublished - May 2005

Keywords

  • Alzheimer's
  • Clusterin
  • Microglia
  • Neurotoxicity
  • Nitric oxide
  • Tumor necrosis factor-α
  • apoJ

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Xie, Z., Harris-White, M. E., Wals, P. A., Frautschy, S. A., Finch, C. E., & Morgan, T. E. (2005). Apolipoprotein J (clusterin) activates rodent microglia in vivo and in vitro. Journal of neurochemistry, 93(4), 1038-1046. https://doi.org/10.1111/j.1471-4159.2005.03065.x