Aging Exacerbates the Brain Response to a Peripheral Immune Stimulus

160 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.Pathogenic agents stimulate macrophages in the periphery to produce pro-inflammatory cytokines (IL-1beta, IL-6, and TNFalpha) that convey a message to the brain to stimulate microglia and elicit sickness behaviors. However, excessive or prolonged release of cytokines can cause severe behavior deficits and neurotoxicity. Because neurobehavioral deficits are exacerbated in elderly during peripheral infections, the goal of this dissertation was to investigate age-related changes in the brain prior to and following a peripheral injection of lipopolysaccharide (LPS). In the brain of healthy aged mice there was an increase in oxidative stress and IL-6 production, and this was associated with impairments in motor function. When 12-mon-old mice were fed one of three experimental diets for 6-mon formulated to provide a disparate range of antioxidants, mice fed an antioxidant-rich diet had decreased IL-6 production and improved psychomotor coordination compared to mice fed diets adequate or low in antioxidants. These data suggest antioxidants decrease age-related neuroinflammation and attenuate neurobehavioral deficits. The heightened IL-6 may be associated with the increase in MHC class II reported in the hippocampus of aged mice, which suggests constitutive microglial cell activation. This was accompanied by an increase in magnitude and duration of IL-1beta, IL-6, and TNFalpha mRNA following LPS. Because excessive pro-inflammatory cytokines can cause dendritic retraction which may enhance neurobehavioral deficits, we assessed dendritic branching in CA1 hippocampal pyramidal neurons. Interestingly, aged mice injected with LPS had decreased dendritic complexity in the apical tree suggesting less synaptic input. To determine if the decrease in anti-inflammatory cytokine IL-10 in the aged brain plays a role in this heightened inflammation and the associated dendritic degeneration, the inflammatory response after peripheral LPS in young mice deficient in IL-10 was investigated. After LPS, mice deficient in IL-10 had prolonged sickness behaviors and a greater induction of IL-1beta, IL-6, and TNFalpha. in plasma and discrete brain regions. However, LPS did not influence dendritic branching. Collectively, these data suggest age-related changes in the brain may play a role in sensitizing neurons to inflammatory insults, and pharmacological treatments that reduce oxidative stress and pro-inflammatory cytokines during aging may protect neurons from dendritic degeneration.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD