Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation
Inheritance of the human epsilon4 allele of the apolipoprotein (apo) E gene (APOE) significantly increases the risk of developing Alzheimer's disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases. While apoE isoforms differentially interact with amyloid beta (Abeta), a pleiotropic neurotoxin key to AD etiology, more recent work has focused on immune regulation in AD pathogenesis and on the mechanisms of innate immunomodulatory effects associated with inheritance of different APOE alleles.
APOE genotype modulates expression of proximal genes including APOC1, which encodes a small apolipoprotein that is associated with Abeta plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I.
Methods:
ApoC-I concentration in cerebrospinal fluid from control subjects of differing APOE genotypes was quantified by ELISA.
Real-time PCR and ELISA were used to analyze apoC-I mRNA and protein expression, respectively, in liver, serum, cerebral cortex, and cultured primary astrocytes derived from mice with targeted replacement of murine APOE for human APOE epsilon3 or epsilon4. ApoC-I direct modulation of innate immune activity was investigated in cultured murine primary microglia and astrocytes, as well as human differentiated macrophages, using specific toll-like receptor agonists LPS and PIC as well as Abeta.
Results:
ApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with epsilon4 carriers showing significantly less apoC-I in both species.
ApoC-I potently reduced pro-inflammatory cytokine secretion from primary murine microglia and astrocytes, and human macrophages, stimulated with LPS, PIC, or Abeta.
Conclusions:
ApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an epsilon4 allele have decreased expression of apoC-I resulting in increased innate immune activity.
Author: Eiron CudabackXianwu LiYue YangThomas YooKathleen S MontineSuzanne CraftThomas J MontineChristopher Dirk Keene Credits/Source: Journal of Neuroinflammation 2012, 9:192
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