title: Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration.
abstract: Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain's inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6months in Alzheimer's disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals' baseline condition. TNF-α (50μg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1β, TNF-α and CCL2 and translation of IL-1β were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to that in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Edel
authors.initials: E
authors.lastname: Hennessy
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: Gormley
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Lopez-Rodriguez
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Caoimhe
authors.initials: C
authors.lastname: Murray
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: Murray
authors.affiliation: School of Biochemistry & Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: colm.cunningham@tcd.ie.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000150:complications / Q000523:psychology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D055809:Illness Behavior / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000150:complications / Q000523:psychology*; D017096:Prion Diseases / Q000150:complications / Q000523:psychology; D011597:Psychomotor Performance / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha
keywords: Behavior; Delirium; Dementia; Microglia; Sickness; Systemic inflammation; TNF-α