title: Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation.
abstract: BACKGROUND
  Inheritance 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.
  
  
  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 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.
  
  
  RESULTS
  ApoC-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.
  
  
  CONCLUSIONS
  ApoC-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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Yoo
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Christopher Dirk
authors.initials: CD
authors.lastname: Keene
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D053302:Apolipoprotein C-I / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D053302:Apolipoprotein C-I; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D011070:Poly I-C