Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120

Abraham, Jayne; Jang, Saebyeol; Godbout, Jonathan P.; Chen, J.; Kelley, Keith W.; Dantzer, Robert; Johnson, Rodney W.

doi:10.1016/j.neurobiolaging.2006.11.002

Cited by 62 publications

(64 citation statements)

References 29 publications

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“…Indeed, central activation of the innate immune system by intracerebroventricular (i.c.v.) administration of LPS or GP120 caused amplified mRNA expression of inflammatory cytokines, IL-1β, IL-6, and TNFα in aged (22-24 month) mice (Abraham et al 2008;Huang et al 2008). These studies provide evidence that increased proinflammatory cytokine production in the aged brain is not entirely dependent on an altered peripheral immune system and can be attributed to a reactive glial population.…”

Section: Age-related Changes In the Cns Immune Systemmentioning

confidence: 62%

“…In the studies discussed above, peripheral or central immune stimulation with LPS caused protracted neuroinflammation in the brain of aged rodents. This was paralleled by a prolonged sickness response with protracted anorexia, lethargy, and social withdrawal (Godbout et al 2005;Abraham et al 2008;Huang et al 2008). An amplified sickness response was also detected in older rats that were infected subcutaneously with E. coli.…”

Section: Impaired Anti-inflammatory Feedback In the Aged Brainmentioning

confidence: 99%

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Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Corona

Fenn

Godbout

2011

J Neuroimmune Pharmacol

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A hallmark of the aged immune system is impaired immunoregulation of the innate and adaptive immune system in the periphery and also in the central nervous system (CNS). Impaired immunoregulation may predispose older individuals to an increased frequency of peripheral infections with concomitant cognitive and behavioral complications. Thus, normal aging is hypothesized to alter the highly coordinated interactions between the immune system and the brain. In support of this notion, mounting evidence in rodent models indicate that the increased inflammatory status of the brain is associated with increased reactivity of microglia, the innate immune cells of the CNS. Understanding how immunity is affected with age is important because CNS immune cells play an integral role in propagating inflammatory signals that are initiated in the periphery. Increased reactivity of microglia sets the stage for an exaggerated inflammatory cytokine response following activation of the peripheral innate immune system that is paralleled by prolonged sickness, depressive-like complications and cognitive impairment. Moreover, amplified neuroinflammation negatively affects several aspects of neural plasticity (e.g., neurogenesis, long-term potentiation, and dendritic morphology) that can contribute to the severity of neurological complications. The purpose of this review is to discuss several key peripheral and central immune changes that impair the coordinated response between the immune system and the brain and result in behavioral and cognitive deficits.

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Section: Age-related Changes In the Cns Immune Systemmentioning

confidence: 62%

Section: Impaired Anti-inflammatory Feedback In the Aged Brainmentioning

confidence: 99%

Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Corona

Fenn

Godbout

2011

J Neuroimmune Pharmacol

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“…In some instances, however, peripheral infection results in an exaggerated brain cytokine response and behavioral pathology. For example, old mice that expressed high levels of inflammatory cytokines in the brain after peripheral injection of LPS remained anorectic longer (4), exhibited depression-like behavior longer (5), and experienced deficits in hippocampaldependent working memory not seen in young adult cohorts (6). Peripheral infection also exacerbated neurodegeneration in animal models of multiple sclerosis, Alzheimer's disease, and prion disease by inducing an exaggerated inflammatory cytokine response in the brain (7).…”

Section: Ipopolysaccharide (Lps) Is An Outer Membrane Componentmentioning

confidence: 99%

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

Jang¹,

Kelley

Johnson

2008

Proc. Natl. Acad. Sci. U.S.A.

306

192

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Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-B and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-B DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of I B-␣ but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.cytokines ͉ flavonoids ͉ MAPK ͉ brain ͉ neuroinflammation

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“…In this paper, we show that HIV-1gp120 significantly potentiates IL-1β-mediated increase in CD38 expression and function. HIV1gp120 is known to stimulate IL-1β production in vivo (Abraham et al 2008;Russo et al 2007), which reflects the total production of IL-1β, i.e., microglia and astrocytes. It has also been reported that astrocytes upon treatment with HIV-1gp120 can lead to IL-1β production (Milligan et al 2001;Ronaldson and Bendayan 2006).…”

Section: Cd38-cadpr-mediated Ca 2+ Regulation In Activated Astrocytesmentioning

confidence: 99%

CD38/Cyclic ADP-Ribose Regulates Astrocyte Calcium Signaling: Implications for Neuroinflammation and HIV-1-Associated Dementia

Banerjee

Walseth

Borgmann

et al. 2008

J Neuroimmune Pharmacol

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CD38 is a 45-kD ectoenzyme involved in the synthesis of potent calcium (Ca(2+))-mobilizing agents, cyclic adenosine diphosphate-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+). In HIV-1-infected patients, increased CD38 expression on CD8+ T cells is linked to immune system activation and progression of HIV-1 infection. However, the role of CD38 upregulation in astrocyte function and HIV-1-associated dementia (HAD-now called HAND: HIV-1-associated neurocognitive disorder) neuropathogenesis is unclear. To these ends, we used interleukin (IL)-1beta and HIV-1gp120 to activate primary human astrocytes and measured CD38 expression using real-time polymerase chain reaction and CD38 function by ADP-ribosyl cyclase activity. We also determined cADPR-mediated changes in single-cell intracellular Ca(2+) transients in activated astrocytes in presence or absence of ethylene glycol tetraacetic acid. CD38 levels were downregulated using CD38 small-interfering RNA (siRNA) and intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured. We previously reported a approximately 20-fold rise in CD38 messenger RNA levels in IL-1beta-activated astrocytes. We extend this observation and report that HIV-1gp120 potentiated CD38 expression in a dose-dependent manner and also increased CD38 enzyme activity in control and IL-1beta-activated astrocytes. We demonstrate higher cADPR levels in IL-1beta-activated astrocytes with a corresponding rise in [Ca(2+)](i) upon cADPR application and its non-hydrolysable analog, 3-deaza-cADPR. In activated astrocytes, pre-treatment with the cADPR-specific antagonist 8-Br-cADPR and CD38 siRNA transfection returned elevated [Ca(2+)](i) to baseline, thus confirming a CD38-cADPR specific response. These data are important for unraveling the mechanisms underlying the role of astrocyte-CD38 in HAD and have broader implications in other inflammatory diseases involving astrocyte activation and CD38 dysregulation.

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Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120

Cited by 62 publications

References 29 publications

Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

CD38/Cyclic ADP-Ribose Regulates Astrocyte Calcium Signaling: Implications for Neuroinflammation and HIV-1-Associated Dementia

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