In the senescent brain, microglial cells display a more activated phenotype and are hypersensitive to messages emerging from immune-to-brain signaling pathways. Thus, in old individuals with an infection, microglia over react to signals from the peripheral immune system and produce excessive levels of pro- inflammatory cytokines causing behavioral pathology including serious deficits in cognition. In several neurodegenerative diseases, microglial activation has been linked to intracellular reactive oxygen species that act as second messengers and stimulate redox-sensitive transcription factors (e.g., NF?B and AP-1) that control pro-inflammatory genes. Thus, regulating oxidative stress in microglia represents a potential therapeutic approach to not only reducing age-related oxidative damage but also the expression of pro- inflammatory genes, which has been shown to increase with age. To this end, the goal of the proposed research is to investigate if activation of the antioxidant response pathway in microglia reduces neuroinflammation in the senescent brain and prevents excessive production of pro-inflammatory cytokines during infection. The specific hypothesis is that dysfunctional Nuclear factor E2-related factor 2 (Nrf2) signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and that activation of Nrf2 with isothiocyanate sulforaphane (SFN)-a naturally occurring compound in cruciferous vegetables-will prevent the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. The research plan begins by assessing Nrf2 signaling, antioxidant response element (ARE) target genes, oxidative stress and inflammation in the brain of old mice and in microglia isolated from old mice. Subsequent studies will determine if activating Nrf2 with SFN reduces basal levels of oxidative stress and inflammation in brain as well as the reactivity of microglia to signals from the peripheral immune system during infection. Finally, we will determine if activating Nrf2 protects old mice against infection-related behavioral pathology and neuronal injury. This study will be the first to determine if dysfunctional Nrf2-ARE signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and if activation of the Nrf2-ARE pathway prevents the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection.

Public Health Relevance

The goal of the proposed research is to determine if oxidative stress caused by a dysfunctional antioxidant homeostatic response leads to microglial cell priming in the senescent brain. Our specific hypothesis is that dysfunctional Nuclear factor E2-related factor 2 (Nrf2) signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and that activation of Nrf2 with sulforaphane-a naturally occurring compound in cruciferous vegetables-will prevent the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. The proposed research is important for developing new strategies for protecting cognitive health in older adults.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016710-13
Application #
8508769
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Mackiewicz, Miroslaw
Project Start
2000-04-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2013
Total Cost
$301,470
Indirect Cost
$107,745
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Burton, Michael D; Rytych, Jennifer L; Freund, Gregory G et al. (2013) Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice. Brain Behav Immun 30:66-72
Jurgens, Heidi A; Johnson, Rodney W (2012) Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp Neurol 233:40-8
Lynch, Marina A; Johnson, Rodney W (2012) The impact of aging on the brain--risk, resilience and repair. Brain Behav Immun 26:714-6
Jurgens, Heidi A; Amancherla, Kaushik; Johnson, Rodney W (2012) Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. J Neurosci 32:3958-68
Burton, Michael D; Sparkman, Nathan L; Johnson, Rodney W (2011) Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior. J Neuroinflammation 8:54
Jang, Saebyeol; Johnson, Rodney W (2010) Can consuming flavonoids restore old microglia to their youthful state? Nutr Rev 68:719-28
Buchanan, J B; Sparkman, N L; Johnson, R W (2010) Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus. Brain Behav Immun 24:502-11
Jang, Saebyeol; Dilger, Ryan N; Johnson, Rodney W (2010) Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr 140:1892-8
Abraham, Jayne; Johnson, Rodney W (2009) Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice. Brain Behav Immun 23:396-401
Richwine, Amy F; Sparkman, Nathan L; Dilger, Ryan N et al. (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23:794-802

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