Age-dependent cytokine responses: trimethyltin hippocampal injury in wild-type, APOE knockout, and APOE4 mice.
In this study, the hippocampal neurotoxicant trimethyltin (TMT) was used to examine possible differential susceptibility associated with the apolipoprotein E genotype. Mice-wild type (C57BL6J), APOE knockout, and APOE4 transgenic-received either saline or TMT (2 mg/kg, ip) at either 21 days or 8 months of age. At both ages, similar mRNA levels were seen in the hippocampus across genotypes for ICAM-1, A20, and MAC-1. GFAP mRNA was higher in the APOE knockouts and APOE4 as compared to wild-type mice. Within 24 h, TMT produced cell death of hippocampal dentate granule neurons and mild astrogliosis in all animals. In 21-day-old mice, TMT exposure significantly increased mRNA levels for ICAM-1 and MIP-1alpha in all genotypes. EB-22, GFAP, TNFalpha, and TGF-beta1 levels were significantly elevated in both wild-type and APOE knockout mice following TMT. At 8 months of age, genotype specific differences were observed. mRNA levels for GFAP, TNFbeta, TNFalpha, and MIP-1alpha were increased in both APOE knockout and APOE4 mice compared to wild-type mice. TMT exposure significantly increased mRNA levels for GFAP and MIP-1alpha in all animals. TNFalpha mRNA levels were increased in wild-type and APOE4 mice while EB22 mRNA levels were increased in both the APOE knockout and APOE4 mice but not wild-type mice. These data suggest an age-dependent effect on both microglia early inflammatory responses to injury associated with the APOE genotype.
Harry
G J
GJ
Neurotoxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Lefebvre d'Hellencourt
C
C
Bruccoleri
A
A
Schmechel
D
D
D000375:Aging / Q000276:immunology*; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012260:Ribonucleases; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014298:Trimethyltin Compounds / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000514:alpha 1-Antichymotrypsin / Q000235:genetics
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008233:Lymphotoxin-alpha; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; D000514:alpha 1-Antichymotrypsin; D018799:Intercellular Adhesion Molecule-1; C046488:trimethyltin; D012260:Ribonucleases