Talk abstracts
Talk on Wednesday 05:00-05:15pm submitted by Diana Norden
Age-related impairments in the dynamic regulation of active microglia by astrocytes
Diana M. Norden (Department of Neuroscience), Paige J. Trojanowski (Department of Neuroscience), Frederick R. Walker (University of Newcastle, Australia), Jonathan P. Godbout (Department of Neuroscience)
Abstract:
Older individuals are at greater risk for infection and concomitant with this they have a higher frequency for developing neurobehavioral complications that negatively affect health and lifespan. Heightened neuroinflammation may be the key mechanism underlying the development of these neuropsychiatric disorders. In aged rodents, the anti-inflammatory cytokine IL-10 is highly expressed in the brain following immune challenge, yet microglial activation is prolonged and behavioral impairments develop. Recently we showed that astrocytes of adult mice express the IL-10 receptor (IL-10R) and that IL-10 re-directs active astrocytes to produce TGFb, which in turn, attenuates the activation of microglia. Therefore, the purpose of this study was to investigate the degree to which these key cytokine interactions between glia are impaired in the aged brain. Morphological analysis of aged microglia indicated a primed baseline inflammatory state, with increased max cell length and cell perimeter. Similarly, morphological analysis of aged astrocytes showed evidence of significant cyotoskeletal re-organization and hypertrophy. Gene arrays confirmed that there was increased expression of the astrocyte inflammatory markers vimentin and GFAP in the hippocampus of aged mice. Moreover, astrocytes from aged mice had reduced surface IL-10R expression compared to adults. Following immune challenge in vivo, adult astrocytes up-regulated IL-10R and TGFb mRNA. Aged astrocytes, however, failed to increase expression of these mediators. This lack of regulation by TGFb was associated with exaggerated expression of pro-inflammatory mediators in aged microglia. Additionally, active microglia cultured ex vivo with adult astrocytes reduced inflammatory markers while those cultured with aged astrocytes did not. In summary, these novel data indicate that astrocytes have an important role in regulating microglia via TGFb signaling and that an impaired IL-10 response in aged astrocytes contributes to age-related deficits in the regulation of active microglia.
Keywords: Neuroinflammation, aging, microglia