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.
Highlights
It has become clear that inflammation contributes to chronic neurodegeneration but its precise roles are not yet clear and there remains no effective treatment for slowing the progression of chronic conditions such as Alzheimer’s and Parkinson’s disease
Administered TNF-a induced a transient deficit in working memory in the T-maze task in ME7 animals, while there were no deficits in normal brain homogenate-injected controls (NBH) animals challenged (Fig. 1)
In the current study we have demonstrated that acutely elevated systemic TNF-a is sufficient to induce acute cognitive dysfunction and exaggerated sickness behavior and this occurs selectively in animals with existing progressive neurodegeneration
Summary
It has become clear that inflammation contributes to chronic neurodegeneration but its precise roles are not yet clear and there remains no effective treatment for slowing the progression of chronic conditions such as Alzheimer’s and Parkinson’s disease. In animal models of chronic neurodegeneration, such superimposed inflammatory activation can produce de novo pathology and has been shown to exacerbate the progression of neurodegenerative disease (Sheng et al, 2003; Kitazawa et al, 2005; Lee et al, 2008; Cunningham et al, 2009; Field et al, 2010; Krstic et al, 2012). The mechanisms by which systemic inflammation exacerbate neurodegeneration remain unclear
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.