Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation

Abstract

BackgroundInheritance of the human ϵ4 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 β (Aβ), 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 Aβ plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I.MethodsApoC-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 ϵ3 or ϵ4. 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 Aβ.ResultsApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with ϵ4 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 Aβ.ConclusionsApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an ϵ4 allele have decreased expression of apoC-I resulting in increased innate immune activity.

Analysis of the Placental Tissue Transcriptome of Normal and Preeclampsia Complicated Pregnancies

“…The statistically significant decrease in the expression of the APOC1 gene in severe PE, which was revealed in the present study, is probably due to the development of oxidative stress in the blood vessels of the placenta or the recently discovered immunosuppressive properties of the C1 apolipoprotein encoded by this gene [52]. It was previously shown that the serum of PE patients has a high level of triglyceride-rich lipoproteins, which can promote endothelial dysfunction [53, 54].…”

Relation between plasma and brain lipids

“…The most significant change due to aging is observed in gene expression levels of APOD [85]; CSF and hippocampal apoD levels are elevated in Alzheimer's disease [86] and correlated with disease severity [87]. ApoC-I colocalizes with amyloid-b plaques in human Alzheimer's disease brain [88], has been suggested to influence neuroinflammation in Alzheimer's disease [89], and may contribute to genetic susceptibility possibly via linkage disequilibrium with APOE e4 [89][90][91]. In Alzheimer's disease mice, Apoa4 deficiency increases amyloid-b load, enhances neuronal loss, accelerates cognitive dysfunction, and increases mortality [92].…”

MALDI-TOF Mass Spectrometric Analysis of Brain Tumor Cyst Fluid Reveals a Protein Peak Corresponding to ApoC1 and LuzP6

“…ApoC1 is coded on chromosome 19q13.32, it is involved in lipoprotein metabolism and because of alternative splicing many transcript variants exist. The gene is activated when monocytes differentiate into macrophages and ApoC1 expression has been shown in cerebral tissue [9].…”