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Systemic TNF-? 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-? 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-? (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-? (50?g/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-? and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1?, TNF-? and CCL2 and translation of IL-1? were higher in ME7+TNF-? than NBH+TNF-? animals. TNF-? 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-? 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.

SUBMITTER: Hennessy E

PROVIDER: S-EPMC5176008 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Hennessy Edel E Gormley Shane S Lopez-Rodriguez Ana Belen AB Murray Caoimhe C Murray Carol C Cunningham Colm C

Brain, behavior, and immunity 20160912

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 th ...[more]

PMID: 27633985

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Project description:Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2-3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient's derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.

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

Publications

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

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