title: Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolysaccharide.
abstract: A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Kawamoto
authors.forename: C
authors.initials: C
authors.lastname: Scavone
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: S
authors.initials: S
authors.lastname: Camandola
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D003474:Curcumin