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.
Highlights
Inheritance of the human E4 allele of the apolipoprotein E gene (APOE) significantly increases the risk of developing Alzheimer’s disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases
Gamma-induced protein 10 (IP-10), keratinocyte-derived chemokine (KC), leukemia inhibitory factor (LIF), lipopolysaccharide-induced CXC chemokine (LIX), monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-cerebrospinal fluid (CSF)), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, regulated upon activation normal T-cell expressed and secreted (RANTES), Tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) (Millipore, Billercia, MA, USA)
APOE4 mice One group has reported that Apolipoprotein C-I (apoC-I) mRNA is consistently lower in frontal cortex of brains from control and AD patients that harbor the APOC1 H2 allele compared with patients with the APOC1 H1 allele; while human brain regional apoC-I protein in controls was lower in association with APOC1 H2 allele the opposite association was observed in patients with AD [26]
Summary
Inheritance of the human E4 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. APOE genotype has been associated with disease risk or clinical outcome of other neurodegenerative diseases such as vascular dementia, Parkinson’s disease, and dementia with Lewy bodies as described in a recent review [11], suggesting mechanisms, in addition to modulation of Aβ trafficking, by which apoE isoforms may influence neurodegenerative processes. Common to this diverse group of neuropathologies is innate immune activation [12,13,14]. Transgenic mice expressing the human E4 allele show reduced apoE levels compared to E3 animals [20], suggesting a possible mechanism for the apoE isoform-specific regulation of CNS cytokine secretion observed in vivo [21]
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