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


RESULTS
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.


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.
Division of Geriatric Medicine, Department of Medicine, University of California San Diego, La Jolla, California, USA. ladugan@ucsd.edu
Laura L
LL
Dugan
Sameh S
SS
Ali
Grigoriy
G
Shekhtman
Amanda J
AJ
Roberts
Jacinta
J
Lucero
Kevin L
KL
Quick
M Margarita
MM
Behrens
D000375:Aging / Q000502:physiology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D007395:Interneurons / Q000201:enzymology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D016548:Prosencephalon / Q000201:enzymology* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015850:Interleukin-6; D008562:Membrane Glycoproteins; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D013482:Superoxide Dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases