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

Hennessy, Edel; Gormley, S.; López-Rodríguez, Ana Belén; Murray, Caoimhe; Murray, Carol; Cunningham, Colm

doi:10.1016/j.bbi.2016.09.011

Cited by 114 publications

(76 citation statements)

References 70 publications

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“…The IL-1β experiment showed an interaction of disease and treatment (F 1,53 =5.42, p=0.0236) and ME7+saline and ME7+IL-1β animals were significantly different at 1 and 3 hours (p<0.05). As previously described (Hennessy et al, 2017), Bonferroni post-hoc analysis showed that ME7+TNF-α animals were significantly different from both NBH+TNF-α and from ME7+saline at 1 hour after a significant interaction of disease, treatment and time in 3-way ANOVA analysis (F=3.09, df 6,328, p<0.01).…”

Section: Lps Differentially Affects Working Memory In Vulnerable Animsupporting

confidence: 67%

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Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Skelly

Griffin

Murray

et al. 2017

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Section: Lps Differentially Affects Working Memory In Vulnerable Animsupporting

confidence: 67%

“…Group sizes were as follows: NBH+saline (n=16), NBH+TNF (n=11), NBH+IL-1β (n=14), ME7+saline (n=20), ME7+TNF (n=12),ME7+IL-1β (n=12). Data pertaining to TNF-α originally published inHennessy et al, 2017, BBI, 10.1016/j.bbi.2016.09.011(Hennessy et al, 2017). Significant main effects and interactions are described in the main text.…”

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confidence: 99%

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Skelly

Griffin

Murray

et al. 2017

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“…Nonetheless, the NLRP3 inflammasome, an enzyme complex responsible for cleavage and maturation of IL-1 is activated and influences amyloidosis and cognitive function in the APP/PS1 model of AD (Heneka et al 2012;Venegas et al 2017). We previously showed that microglia are 'primed' by primary neuropathology to produce exaggerated acute neuroinflammatory responses to secondary acute stimulation with bacterial endotoxin (Cunningham et al 2005), double stranded RNA (Field et al 2010) and inflammatory cytokines IL-1 and TNFα (Hennessy et al 2017). Such switching of glial phenotypes may release the restraint on microglia during neurodegeneration to induce a more classically activated microglial phenotype which may be an important component of the contribution of systemic inflammation to disease-associated outcomes such as neuronal damage and cognitive decline Holmes et al 2009;Semmler et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

López-Rodríguez

Hennessy

Murray

et al. 2018

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Acknowledgements. This study was supported by a Wellcome Trust Senior ResearchFellowship to CC (SRF090907) and by NIH R01AG050626. The technical assistance of Gavin MacManus in the Biomedical Sciences Imaging suite is gratefully acknowledged. AbstractAlzheimer's disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by -amyloid pathology to induce exaggerated IL-1 responses to acute stimulation with LPS or IL-1. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1 induction nor NFĸB p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1, NFĸB-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1 we demonstrate that astrocytes proximal to A-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

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“…For example, there is evidence to show that conditions such as sepsis and hip fracture cause changes in inflammatory markers [177,178], however, there is little evidence about whether delirium self-propagates. Some animal model data in delirium suggests that there might be a direct impact of inflammatory markers on brain dysfunction [179]. To our knowledge there was no published relationship between tumor markers and neurological brain dysfunction.…”

Section: Discussionmentioning

confidence: 80%

A systematic review of the overlap of fluid biomarkers in delirium and advanced cancer-related syndromes

et al. 2020

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Background: Delirium is a serious and distressing neurocognitive disorder of physiological aetiology that is common in advanced cancer. Understanding of delirium pathophysiology is largely hypothetical, with some evidence for involvement of inflammatory systems, neurotransmitter alterations and glucose metabolism. To date, there has been limited empirical consideration of the distinction between delirium pathophysiology and that of the underlying disease, for example, cancer where these mechanisms are also common in advanced cancer syndromes such as pain and fatigue. This systematic review explores biomarker overlap in delirium, specific advanced cancerrelated syndromes and prediction of cancer prognosis. Methods: A systematic review (PROSPERO CRD42017068662) was conducted, using MEDLINE, PubMed, Embase, CINAHL, CENTRAL and Web of Science, to identify body fluid biomarkers in delirium, cancer prognosis and advanced cancer-related syndromes of interest. Studies were excluded if they reported delirium tremens only; did not measure delirium using a validated tool; the sample had less than 75% of participants with advanced cancer; measured tissue, genetic or animal biomarkers, or were conducted post-mortem. Articles were screened for inclusion independently by two authors, and data extraction and an in-depth quality assessment conducted by one author, and checked by two others. Results: The 151 included studies were conducted in diverse settings in 32 countries between 1985 and 2017, involving 28130 participants with a mean age of 69.3 years. Seventy-one studies investigated delirium biomarkers, and 80 studies investigated biomarkers of an advanced cancer-related syndrome or cancer prognosis. Overall, 41 biomarkers were studied in relation to both delirium and either an advanced cancer-related syndrome or prognosis; and of these, 24 biomarkers were positively associated with either delirium or advanced cancer syndromes/ prognosis in at least one study. The quality assessment showed large inconsistency in reporting. Conclusion: There is considerable overlap in the biomarkers in delirium and advanced cancer-related syndromes. Improving the design of delirium biomarker studies and considering appropriate comparator/controls will help to better understanding the discrete pathophysiology of delirium in the context of co-existing illness.

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

Abstract: Graphical abstract

Cited by 114 publications

References 70 publications

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

A systematic review of the overlap of fluid biomarkers in delirium and advanced cancer-related syndromes

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