Differential response of apoptosis-regulatory Bcl-2 and Bax proteins to an inflammatory challenge in the cerebral cortex and hippocampus of aging mice.
Apoptosis plays a key role in normal aging and neurodegeneration. It is now known that normal aging implies low-grade inflammation and increases susceptibility to neurodegenerative diseases, which, in turn, include a neuroinflammatory component. We here investigated, using mice of 2-3 months, 10-11 months, or 18-21 months of age, the expression of apoptosis-regulatory proteins in cortical brain regions in response to intracerebroventricular administration of pro-inflammatory cytokines. A mixture of interferon-gamma and tumor necrosis factor-alpha was injected, using vehicle (phosphate-buffered saline) as control. At 4 days, levels of the anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins in the cerebral cortex and hippocampus, examined with Western blotting, were markedly upregulated by cytokine exposure in mice of all age groups with respect to controls. Interestingly, cytokine-elicited Bcl-2 upregulation was aging-dependent, with significant enhancement paralleling the animals' age. Cytokine-elicited Bax expression did not exhibit instead significant aging-related variation. Using the same paradigm and 1 or 2 day survival, Bcl-2 immunoreactivity was observed mainly in neurons of cortex and hippocampus of both control and cytokine-treated mice of all age groups. Furthermore, immunohistochemistry confirmed the enhancement of cytokine-elicited Bcl-2 expression in the cerebral cortex and hippocampus of old mice, and showed that this finding was already evident in the second day after cytokine exposure. The data point out the novel finding that Bcl-2 and Bax expression in cortical brain regions is differentially regulated during senescence in response to an acute inflammatory challenge. Aging-related Bcl-2 increases in neurons after cytokine exposure could contribute to amplify neuroprotective mechanisms in the old brain.
Xu
Yuan-Zhong
YZ
Department of Morphological and Biomedical Sciences, University of Verona, Verona, Italy.
Deng
Xiao-Hua
XH
Bentivoglio
Marina
M
D000367:Age Factors; D000375:Aging; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D016898:Interferon-alpha; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D016898:Interferon-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein