Proinflammatory cytokines and free radicals contribute to a variety of neurodegenerative pathologies of the elderly, including Alzheimer's disease, Parkinson's and cerebral ischemia. These molecules have also been implicated in age-related changes in normal physiology, such as age-related sleep disorders. Microglia and astrocytes that produce proinflammatory cytokines and nitrogen and oxygen radicals are known to become more """"""""reactive"""""""" with age, as measured by increased in vitro proliferation and decreased responsiveness to their negative regulators. We have demonstrated that in vitro cultures of mixed glia can be established from adult mice and that these cells exhibit age-related increases in tumor necrosis factor-alpha (TNF) after stimulation with the inducer lipopolysaccharide (LPS); cultures from 18-month-old mice produce approximately twice the TNF of cultures from 3-month-old animals. To date, no comprehensive analysis of age-related changes in production and regulation of the pro-inflammatory cytokines TNF, interleukin-1 (IL-1) and IL-6, and reactive nitrogen and oxygen species has been performed. We intend to characterize changes in regulation of production of these inflammatory mediators in murine mixed glial cultures so that age-related changes in glial cell activation can be defined. Cells comprising mixed glial cultures from 3-, 12-, and 24-month-old mice will undergo comprehensive phenotypic analysis, and the effects of various inducers and negative regulators on parameters of interest in such cultures will be examined. We hypothesize that increased production of a variety of inflammatory mediators will be seen in cultures from aged mice, that this increased activation is part of the normal physiology of aging, and that it contributes to the increase in neurodegenerative disease in the elderly. Knowledge of age- related alterations in cytokine and free radical production by glia should provide baseline information for further studies on central nervous system physiology and pathology associated with aging. These data will also assist in the rational design of therapies for neurodegenerative diseases in which these molecules play a role, and have relevance for other functions in which cytokines have been implicated, such as age-related sleep disorders.
| Terao, Akira; Apte-Deshpande, Anjali; Morairty, Stephen et al. (2002) Age-related decline in hypocretin (orexin) receptor 2 messenger RNA levels in the mouse brain. Neurosci Lett 332:190-4 |
