TY - JOUR
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
AU - Hu, Jingru
AU - Guo, Ling
AU - Van Eldik, Linda J.
N1 - Funding Information:
This work was supported in part by National Institutes of Health grants AG16776 (to MJLD), AG13939 (to LVE), AG15501 (to LVE and MJLD), and NS37525 (to GB); a Brain Research Foundation research grant (to GSG); and American Health Assistance Foundation grant 97006 (to GSG).
PY - 2001
Y1 - 2001
N2 - 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.
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.
KW - Alzheimer's disease
KW - Astrocyte
KW - Cytokine
KW - Glial cell
KW - Inflammation
KW - LDLR-related protein
KW - Lipoproteins
KW - Low-density lipoprotein receptor
KW - Receptor associated protein
KW - apoE
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U2 - 10.1016/S0197-0186(01)00050-X
DO - 10.1016/S0197-0186(01)00050-X
M3 - Article
C2 - 11578778
AN - SCOPUS:0034813741
SN - 0197-0186
VL - 39
SP - 427
EP - 434
JO - Neurochemistry International
JF - Neurochemistry International
IS - 5-6
ER -