Poster abstracts

Poster number 92 submitted by Diana Norden

Immune and Behavioral Consequences of Age-Related Impairments in the Dynamic Regulation of Microglia by Astrocytes

Diana M. Norden (Department of Neuroscience), Jonathan P. Godbout (Department of Neuroscience)

Abstract:
In the elderly, peripheral infection is associated with a higher incidence of neuropsychiatric complications, but the mechanisms underlying these complications are unknown. Using a mouse model of aging, we have reported that acute activation of the innate immune system caused an exaggerated neuroinflammatory response and the development of depressive-like behavior in aged mice. These age-related inflammatory deficits may be caused by impaired regulation of central nervous system (CNS) immune cells, called microglia. For example, following immune challenge, aged microglia produce amplified levels of both pro- and anti-inflammatory cytokines. Despite higher levels of Interleukin (IL)-10, an anti-inflammatory cytokine, microglial activation was unresolved in the aged brain. In adult mice, astrocytes express the IL-10 receptor (IL-10R) and increase production of the regulatory molecule Transforming Growth Factor (TGF) b in response to IL-10 treatment. Therefore, the purpose of this study was to investigate the degree to which IL-10 signaling and subsequent TGFb upregulation is impaired in the brain of aged mice. First, we examined astrocytes in adult and aged mice and found that astrocytes in aged mice had increased expression of the inflammatory markers GFAP and vimentin. Astrocytes from aged mice also had decreased IL-10R expression compared to adults. Following immune challenge in vivo, astrocytes from adult mice upregulated IL-10R and TGFb mRNA. Astrocytes from aged mice, however, failed to upregulate both IL-10R and TGFb mRNA. This lack of regulation by TGFb was associated with exaggerated pro-inflammatory gene expression and neuroinflammation. These data indicate that astrocytes from aged mice are more inflammatory and less sensitive to IL-10, and in turn, TGFb is not upregulated following immune challenge. Future studies will use AAV9 gene delivery to enhance IL-10R expression preferentially on astrocytes to restore IL-10 responsiveness and TGFb production.

Keywords: Microglia, Astrocytes, neuroinflammation