IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase

• Published in: PloS one Vol. 4; no. 5; p. e5518
• Main Authors: Dugan, Laura L, Ali, Sameh S, Shekhtman, Grigoriy, Roberts, Amanda J, Lucero, Jacinta, Quick, Kevin L, Behrens, M Margarita
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-05-2009; Public Library of Science (PLoS)
• Subjects: Age; Aging; Aging - physiology; Animals; Apnea; Arteriosclerosis; Atherosclerosis; Brain; Cell Biology/Neuronal and Glial Cell Biology; Cell Biology/Neuronal Signaling Mechanisms; Cell Nucleus - metabolism; Central nervous system; Cognition - physiology; Cognitive ability; Cognitive tasks; Cytokines; Data processing; Degeneration; Diabetes mellitus; Digital video; Drugs; Forebrain; GABA; gamma-Aminobutyric Acid - metabolism; Gene deletion; Geriatrics; Hypertension; Immunology/Immune Response; Immunology/Immunomodulation; Immunology/Innate Immunity; Immunosuppressive agents; Inflammation; Information processing; Information retrieval; Interleukin; Interleukin 6; Interleukin-6 - metabolism; Interleukins; Interneurons; Interneurons - enzymology; Interneurons - metabolism; Kinases; Medicine; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Memory; Mice; Mice, Transgenic; NAD(P)H oxidase; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Nerve Degeneration - enzymology; Nervous system; Neurodegeneration; Neurons; Neurons - enzymology; Neurons - metabolism; Neuroscience; Neuroscience/Animal Cognition; Neuroscience/Neurobiology of Disease and Regeneration; Neuroscience/Neuronal Signaling Mechanisms; NF-κB protein; Obesity; Older people; Oxidase; Oxidases; Parvalbumin; Parvalbumins - metabolism; Patients; Physiological aspects; Plasma; Plasma levels; Prosencephalon - enzymology; Prosencephalon - metabolism; Rodents; Sleep; Sleep apnea syndromes; Sleep disorders; Spatial discrimination learning; Spatial memory; Studies; Superoxide; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Synaptosomes - metabolism; Trends; γ-Aminobutyric acid; La Jolla California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005518

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.
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 NFkappaB 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.
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.