Increasing evidence indicates that adverse health outcomes in older adults are strongly associated with the development of a state of chronic, mild inflammation. In humans, circulating markers of inflammation, including the inflammatory cytokine interleukin-6 (IL-6), are associated with, or predict, enhanced risk of frailty, loss of muscle mass and strength, disability, and early mortality, as well as acute and chronic cognitive decline, development of Alzheimer's disease, and drug- and stress-induced delirium. IL-6 activates a host of inflammatory actions through classical Jak/STAT pathway, but we recently found that IL-6, acting through non-cannonical activation of the transcription factor, NFkB, induces neuronal expression and activation of NADPH oxidase (Nox2), a multimeric enzyme complex first described as the respiratory burst oxidase in neutrophils. Nox2 is designed to produce large amounts of reactive oxygen species (ROS), primarily superoxide anion. We have further shown that Nox2 is induced and activated in neurons in the aging brain, and that Nox2 is in fact the major source of neuronal and synaptic superoxide production in aged mice. Inflammatory induction of Nox2 led to a superoxide-dependent loss of subsets of inhibitory interneurons in hippocampus, cortex, and amygdala. Loss of these neurons is observed in rodents, dogs, and primates, and has been proposed to underlie cognitive deficits across cognitive domains. We will test the hypothesis that age-related increase in IL-6, potentially mediated by the inflammatory cytokine TNFa or loss of the anti-inflammatory cytokine IL-10, induces neuronal Nox2 expression and that Nox2, in turn, results in persistent deficits in inhibitory neural circuits required for learning, attention, and memory encoding. Aged wild-type mice, and aged mice with modifications (either genetic or pharmacologic) which modify IL-6 expression, signaling, or specific downstream targets, will be used to test our hypothesis. A variety of techniques, including live animal fluorescence imaging of Nox2 activity, EPR, confocal imaging, immuno-fluorescence, electrophysiology and behavioral testing of brain region-specific function (e.g. spatial learning, a hippocampal CA3-dependent process) will be used to test each link in our hypothesized sequence. Finally, a series of interventional studies with drugs and immunotherapies which modulate IL-6, or the proposed sequence of events, will be carried out to determine whether age-related cognitive deficits in the mice are ameliorated, and to further test our hypothetical sequence. Importance to Human Health: Changes in cognitive function are an important health concern for older adults, and for society. The link between inflammatory pathway activation and aging in the brain remains to be fully defined. The studies proposed here are designed to explore one pathway which may link inflammatory pathways and age-related cognitive deficits, with the potential to provide additional insights into important and possibly reversible biological and neural circuitry changes in the aging brain.
Older adults are more vulnerable to the development of adverse cognitive outcomes, including decline in cognitive function and the development of delirium, after acute illness, surgery, and other stressors. The exact etiology and molecular mechanisms are not known, but recent studies suggest a role for the pro- inflammatory cytokine interleukin-6 (IL-6) in many aging-related disorders, including cognitive vulnerability. Our project seeks to determine the mechanisms which underlie the association between systemic inflammation, IL-6, and cognitive vulnerability, and to try to determine whether interventions which target IL-6 or downstream pathways might prevent age-related cognitive decline.
|Hardt, Joshua I; Perlmutter, Joel S; Smith, Christopher J et al. (2018) Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates. Eur J Drug Metab Pharmacokinet 43:543-554|
|Hou, Catherine; Hsieh, Chia-Ju; Li, Shihong et al. (2018) Development of a Positron Emission Tomography Radiotracer for Imaging Elevated Levels of Superoxide in Neuroinflammation. ACS Chem Neurosci 9:578-586|
|Dugan, Laura L; Tian, LinLin; Quick, Kevin L et al. (2014) Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates. Ann Neurol 76:393-402|
|Chu, Wenhua; Chepetan, Andre; Zhou, Dong et al. (2014) Development of a PET radiotracer for non-invasive imaging of the reactive oxygen species, superoxide, in vivo. Org Biomol Chem 12:4421-31|
|Naviaux, Robert K; Zolkipli, Zarazuela; Wang, Lin et al. (2013) Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS One 8:e57380|
|Dugan, Laura L; You, Young-Hyun; Ali, Sameh S et al. (2013) AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 123:4888-99|
|Hall, David J; Han, Sung-Ho; Chepetan, Andre et al. (2012) Dynamic optical imaging of metabolic and NADPH oxidase-derived superoxide in live mouse brain using fluorescence lifetime unmixing. J Cereb Blood Flow Metab 32:23-32|
|Pamenter, Matthew E; Ali, Sameh S; Tang, Qingbo et al. (2012) An in vitro ischemic penumbral mimic perfusate increases NADPH oxidase-mediated superoxide production in cultured hippocampal neurons. Brain Res 1452:165-72|
|Ali, Sameh S; Young, Jared W; Wallace, Chelsea K et al. (2011) Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice. Brain Res 1368:65-70|
|Douglas, Robert M; Ryu, Julie; Kanaan, Amjad et al. (2010) Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction. Am J Physiol Cell Physiol 298:C1594-602|
Showing the most recent 10 out of 11 publications