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 D Bu, Jingru Hu, Ling Guo, Linda J. Van Eldik

Research output: Contribution to journalArticle

89 Citations (Scopus)

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 - 2001
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Apolipoproteins E
Neuroglia
LDL Receptors
LDL-Receptor Related Proteins
Proteins
Apolipoproteins
Amyloid
Knockout Mice
Astrocytes
Neurodegenerative Diseases
Lipopolysaccharides
Alzheimer Disease
Oxidative Stress
Anti-Inflammatory Agents
Cytokines
Neurons

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses. / LaDu, Mary Jo; Shah, Javeed Ali; Reardon, Catherine A.; Getz, Godfrey S.; Bu, Guojun D; Hu, Jingru; Guo, Ling; Van Eldik, Linda J.

In: Neurochemistry International, Vol. 39, No. 5-6, 2001, p. 427-434.

Research output: Contribution to journalArticle

LaDu, Mary Jo ; Shah, Javeed Ali ; Reardon, Catherine A. ; Getz, Godfrey S. ; Bu, Guojun D ; Hu, Jingru ; Guo, Ling ; Van Eldik, Linda J. / Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses. In: Neurochemistry International. 2001 ; Vol. 39, No. 5-6. pp. 427-434.
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T1 - Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses

AU - LaDu, Mary Jo

AU - Shah, Javeed Ali

AU - Reardon, Catherine A.

AU - Getz, Godfrey S.

AU - Bu, Guojun D

AU - Hu, Jingru

AU - Guo, Ling

AU - Van Eldik, Linda J.

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AB - 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.

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