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Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration

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Hennessy, Edel and Gormley, Shane and López Rodríguez, Ana Belén and Murray, Caoimhe and Murray, Carol and Cunningham, Colm (2017) Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain, Behavior, and Immunity, 59 . pp. 233-244. ISSN 0889-1591

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Official URL: https://www.journals.elsevier.com/brain-behavior-and-immunity/



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 6 months 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 (50 μg/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.


Item Type:Article
Uncontrolled Keywords:TNF-α, Systemic inflammation, Microglia, Sickness, Behavior, Dementia, Delirium
Subjects:Medical sciences > Biology
Medical sciences > Biology > Animal physiology
Medical sciences > Biology > Mammals
Medical sciences > Biology > Neurosciences
ID Code:44433
Deposited On:01 Sep 2017 07:17
Last Modified:04 Sep 2017 11:47

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