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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.