Background Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. Methods and Findings We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6？/？ mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFκB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. Conclusions Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.
References
[1]
Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39: 687–699.
[2]
Maggio M, Guralnik JM, Longo DL, Ferrucci L (2006) Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci 61: 575–584.
[3]
Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51: 245–270.
[4]
Giuliani N, Sansoni P, Girasole G, Vescovini R, Passeri G, et al. (2001) Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 36: 547–557.
[5]
Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, et al. (2006) Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 54: 991–1001.
[6]
Sarkisian CA, Gruenewald TL, John Boscardin W, Seeman TE (2008) Preliminary Evidence for Subdimensions of Geriatric Frailty: The MacArthur Study of Successful Aging. J Am Geriatr Soc 56: 2292–2297.
[7]
Bermejo P, Martin-Aragon S, Benedi J, Susin C, Felici E, et al. (2008) Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett 117: 198–202.
[8]
Marsland AL, Petersen KL, Sathanoori R, Muldoon MF, Neumann SA, et al. (2006) Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med 68: 895–903.
[9]
Sarkar D, Fisher PB (2006) Molecular mechanisms of aging-associated inflammation. Cancer Lett 236: 13–23.
[10]
Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9: 4653–4665.
[11]
Boulanger MJ, Chow DC, Brevnova EE, Garcia KC (2003) Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300: 2101–2104.
[12]
Cartmell T, Poole S, Turnbull AV, Rothwell NJ, Luheshi GN (2000) Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol 526 Pt 3: 653–661.
[13]
Qiu Z, Gruol DL (2003) Interleukin-6, beta-amyloid peptide and NMDA interactions in rat cortical neurons. J Neuroimmunol 139: 51–57.
[14]
Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, et al. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90: 10061–10065.
[15]
Behrens MM, Ali SS, Dugan LL (2008) Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci 28: 13957–13966.
[16]
Hu D, Klann E, Thiels E (2007) Superoxide dismutase and hippocampal function: age and isozyme matter. Antioxid Redox Signal 9: 201–210.
[17]
Kishida KT, Hoeffer CA, Hu D, Pao M, Holland SM, et al. (2006) Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease. Mol Cell Biol 26: 5908–5920.
[18]
Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, et al. (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons Is mediated by NADPH-oxidase. Science 318: 1645–1647.
[19]
Paulsen O, Moser E (1998) A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends in Neurosciences 21: 273–278.
[20]
Wallenstein GV, Hasselmo ME (1997) GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect. J Neurophysiol 78: 393–408.
[21]
Gazzaley A, Cooney JW, Rissman J, D'Esposito M (2005) Top-down suppression deficit underlies working memory impairment in normal aging. Nat Neurosci 8: 1298–1300.
[22]
Luebke JI, Rosene DL (2003) Aging alters dendritic morphology, input resistance, and inhibitory signaling in dentate granule cells of the rhesus monkey. J Comp Neurol 460: 573–584.
[23]
Bu J, Sathyendra V, Nagykery N, Geula C (2003) Age-related changes in calbindin-D28k, calretinin, and parvalbumin-immunoreactive neurons in the human cerebral cortex. Exp Neurol 182: 220–231.
[24]
Pugliese M, Carrasco JL, Geloso MC, Mascort J, Michetti F, et al. (2004) Gamma-aminobutyric acidergic interneuron vulnerability to aging in canine prefrontal cortex. J Neurosci Res 77: 913–920.
[25]
Vela J, Gutierrez A, Vitorica J, Ruano D (2003) Rat hippocampal GABAergic molecular markers are differentially affected by ageing. J Neurochem 85: 368–377.
[26]
Ye SM, Johnson RW (2001) Regulation of interleukin-6 gene expression in brain of aged mice by nuclear factor kappaB. J Neuroimmunol 117: 87–96.
[27]
Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, et al. (2008) A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging 29: 117–128 Epub Oct. 2006.
[28]
Serrano F, Kolluri NS, Wientjes FB, Card JP, Klann E (2003) NADPH oxidase immunoreactivity in the mouse brain. Brain Res 988: 193–198.
[29]
Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG (2006) Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 18: 69–82.
[30]
Serrander L, Cartier L, Bedard K, Banfi B, Lardy B, et al. (2007) NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J 406: 105–114.
[31]
Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87: 245–313.
[32]
Serrander L, Cartier L, Bedard K, Banfi B, Lardy B, et al. (2007) NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J.
[33]
Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7: 30–40.
[34]
Magnusson KR, Scruggs B, Aniya J, Wright KC, Ontl T, et al. (2003) Age-related deficits in mice performing working memory tasks in a water maze. Behav Neurosci 117: 485–495.
[35]
Bai L, Hof PR, Standaert DG, Xing Y, Nelson SE, et al. (2004) Changes in the expression of the NR2B subunit during aging in macaque monkeys. Neurobiol Aging 25: 201–208.
[36]
Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, et al. (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF{kappa}B. Genes Dev.
[37]
de Erausquin GA, Hyrc K, Dorsey DA, Mamah D, Dokucu M, et al. (2003) Nuclear translocation of nuclear transcription factor-kappa B by alpha-amino-3-hydroxy-5-methyl-4-isoxazo？lepropionicacid receptors leads to transcription of p53 and cell death in dopaminergic neurons. Mol Pharmacol 63: 784–790.
[38]
Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8: 45–56.
[39]
Ershler WB (1993) Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 41: 176–181.
[40]
Heumuller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, et al. (2008) Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension 51: 211–217.
[41]
Jackman KA, Miller AA, De Silva TM, Crack PJ, Drummond GR, et al. (2009) Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br J Pharmacol 156: 680–688.
Choi DK, Pennathur S, Perier C, Tieu K, Teismann P, et al. (2005) Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice. J Neurosci 25: 6594–6600.
[44]
Maki RA, Tyurin VA, Lyon RC, Hamilton RL, DeKosky ST, et al. (2009) Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease. J Biol Chem 284: 3158–3169.
[45]
Everse J, Coates PW (2007) Neurodegeneration and peroxidases. Neurobiol Aging.
[46]
Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, et al. (1993) Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol 150: 5219–5230.
[47]
Keller ET, Wanagat J, Ershler WB (1996) Molecular and cellular biology of interleukin-6 and its receptor. Front Biosci 1: d340–357.
[48]
Ali SS, Xiong C, Lucero J, Behrens MM, Dugan LL, et al. (2006) Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress. Aging Cell 5: 565–574.
[49]
Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8: 1583–1596.
[50]
Thiels E, Klann E (2002) Hippocampal memory and plasticity in superoxide dismutase mutant mice. Physiol Behav 77: 601–605.
[51]
Kishida KT, Klann E (2007) Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal 9: 233–244.
[52]
Hunsaker MR, Rosenberg JS, Kesner RP (2008) The role of the dentate gyrus, CA3a,b, and CA3c for detecting spatial and environmental novelty. Hippocampus 18: 1064–1073.
[53]
Kausler DH (1994) Learning and Memory in Normal Aging. Academic Press, San Diego, CA.
[54]
Kesner RP (2007) Behavioral functions of the CA3 subregion of the hippocampus. Learn Mem 14: 771–781.
[55]
Wilson IA, Gallagher M, Eichenbaum H, Tanila H (2006) Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci 29: 662–670.
[56]
Gilbert PE, Kesner RP (2006) The role of the dorsal CA3 hippocampal subregion in spatial working memory and pattern separation. Behav Brain Res 169: 142–149.
[57]
Hunsaker MR, Tran GT, Kesner RP (2008) A double dissociation of subcortical hippocampal efferents for encoding and consolidation/retrieval of spatial information. Hippocampus 18: 699–709.
[58]
Bakker A, Kirwan CB, Miller M, Stark CE (2008) Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319: 1640–1642.
[59]
Driscoll I, Hamilton DA, Yeo RA, Brooks WM, Sutherland RJ (2005) Virtual navigation in humans: the impact of age, sex, and hormones on place learning. Horm Behav 47: 326–335.
[60]
Moffat SD, Zonderman AB, Resnick SM (2001) Age differences in spatial memory in a virtual environment navigation task. Neurobiol Aging 22: 787–796.
[61]
Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, et al. (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26: 1604–1615.
[62]
Hall D, Han S, Dugan LL (2009) In vivo optical imaging of dihydroethidium oxidation in the mouse brain employing fluorescence intensity and lifetime contrast.
[63]
Benice TS, Raber J (2008) Object recognition analysis in mice using nose-point digital video tracking. J Neurosci Methods 168: 422–430.
[64]
Buxbaum JN, Ye Z, Reixach N, Friske L, Levy C, et al. (2008) Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci U S A 105: 2681–2686.
[65]
Prut L, Abramowski D, Krucker T, Levy CL, Roberts AJ, et al. (2007) Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze. Behav Brain Res 179: 107–110.
