Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses

Mary Jo LaDu, Javeed Ali Shah, Catherine A. Reardon, Godfrey S. Getz, Guojun Bu, Jingru Hu, Ling Guo, Linda J. Van Eldik

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Large numbers of activated glia are a common pathological feature of many neurodegenerative disorders, including Alzheimer's disease (AD). Several different stimuli, including lipopolysaccharide (LPS), dibutyryl (db)cAMP, and aged amyloid-β 1-42 (Aβ), can induce glial activation in vitro, as measured by morphological changes and the production of pro-inflammatory cytokines and oxidative stress molecules. Only Aβ-induced activation is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. In addition, only Aβ also induces an increase in the amount of endogenous apoE, the primary apolipoprotein expressed by astrocytes in the brain. The functional significance of the increase in apoE appears to be to limit the inflammatory response. Indeed, compared to wild type mice, glial cells cultured from apoE knockout mice exhibit an enhanced production of several pro-inflammatory markers in response to treatment with Aβ and other activating stimuli. The mechanism for both the Aβ-induced glial activation and the increase in apoE appears to involve apoE receptors, a variety of which are expressed by both neurons and glia. Experiments using receptor associated protein (RAP), an inhibitor of apoE receptors with a differential affinity for the low-density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), revealed that LRP mediates Aβ-induced glial activation, while LDLR mediates the Aβ-induced changes in apoE levels. In summary, both an apoE receptor agonist (apoE) and an antagonist (RAP) inhibit Aβ-induced glial cell activation. Thus, apoE receptors appear to translate the presence of extracellular Aβ into cellular responses, both initiating glial cell activation and limiting its scope by inducing apoE, an anti-inflammatory agent.

Original languageEnglish (US)
Pages (from-to)427-434
Number of pages8
JournalNeurochemistry International
Volume39
Issue number5-6
DOIs
StatePublished - Oct 9 2001

Keywords

  • Alzheimer's disease
  • Astrocyte
  • Cytokine
  • Glial cell
  • Inflammation
  • LDLR-related protein
  • Lipoproteins
  • Low-density lipoprotein receptor
  • Receptor associated protein
  • apoE

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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