Apolipoprotein E and apolipoprotein E receptors modulate A beta-induced glial neuroinflammatory responses.
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-beta 1-42 (A beta), can induce glial activation in vitro, as measured by morphological changes and the production of pro-inflammatory cytokines and oxidative stress molecules. Only A beta-induced activation is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. In addition, only A beta 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 A beta and other activating stimuli. The mechanism for both the A beta-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 A beta-induced glial activation, while LDLR mediates the A beta-induced changes in apoE levels. In summary, both an apoE receptor agonist (apoE) and an antagonist (RAP) inhibit A beta-induced glial cell activation. Thus, apoE receptors appear to translate the presence of extracellular A beta into cellular responses, both initiating glial cell activation and limiting its scope by inducing apoE, an anti-inflammatory agent.
LaDu
M J
MJ
Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1801 Maple Avenue, Suite 6240, Evanston, IL 60201, USA. mjladu@enhri.birl.nwu.edu
Shah
J A
JA
Reardon
C A
CA
Getz
G S
GS
Bu
G
G
Hu
J
J
Guo
L
L
Van Eldik
L J
LJ
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D004660:Encephalitis / Q000503:physiopathology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1