Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis.
The trisomy of human chromosome 21 (Down syndrome) is the leading genetic cause of learning difficulties in children, and predisposes this population to the early onset of the neurodegeneration of Alzheimer's disease. Down syndrome is associated with increased interferon (IFN) sensitivity resulting in unexpectedly high levels of IFN inducible gene products including Fas, complement factor C3, and neuronal HLA I which could result in a damaging inflammatory reaction in the brain. Consistent with this possibility, we report here that the trisomy 16 mouse fetus has significantly increased whole brain IFN-gamma and Fas receptor immunoreactivity and that cultured whole brain trisomy 16 mouse neurons have increased basal levels of caspase 1 activity and altered homeostasis of intracellular calcium and pH. The trisomic neurons also showed a heightened sensitivity to the increase in both Fas receptor levels and caspase 1 activity we observed when IFN-gamma was added to the neuron culture media. Because of the autoregulatory nature of IFN activity, and the IFN inducing capability of caspase-1-activated cytokine activity, our data argue in favor of the possibility of an interferon-mediated, self-perpetuating, inflammatory response in the trisomy brain that could subserve the loss of neuron viability seen in this trisomy 16 mouse model for Down syndrome.
Hallam
D M
DM
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, P.O. Box 19626, Springfield, IL 62794-9626, USA.
Capps
N L
NL
Travelstead
A L
AL
Brewer
G J
GJ
Maroun
L E
LE
D000544:Alzheimer Disease / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001923:Brain Chemistry / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004314:Down Syndrome / Q000276:immunology; D004660:Encephalitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology; D006706:Homeostasis / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D014178:Translocation, Genetic; D014314:Trisomy / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
D019014:fas Receptor; D007371:Interferon-gamma; D020170:Caspase 1; D002118:Calcium