Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

Abstract

Background: Tumour necrosis factor -alpha (TNF-α) is a pro-inflammatory cytokine that combines a plethora of activities in the early stages of an immune response. TNF-α has gained increasing importance given TNF-α upregulation in multiple brain pathologies like neuropsychiatric conditions such as depression, schizophrenia, as well as neuroinflammatory disorder like multiple sclerosis (MS). Aim: The aim of this review is to critically analyse neurobiological, immunological and molecular mechanisms through which TNF-α influences the development of cognitive dysfunction. Principal findings/results: The review presents several lines of original research showing that the immunological properties of TNF-α exacerbate inflammatory responses in the central nervous system such as microglial and endothelial activation, lymphocytic and monocytic infiltration and the expression of downstream pro-inflammatory cytokines and apoptotic factors. Depression, schizophrenia, and MS all manifest symptoms of activated immune response along with cognitive dysfunction, with TNF-α overexpression as a central clinical feature common to these disorders. Furthermore, TNF-α acts negatively on neuroplasticity and the molecular mechanisms of memory and learning (i.e., long-term potentiation and long-term depression). TNF-α also exerts influence over the production of neurotrophins (i.e., nerve growth factor and brain-derived neurotrophic factor), neurogenesis, and dendritic branching. Conclusions/significance: This review outlines that TNF-α and its receptors have a substantial yet underappreciated influence on the development and progression of neuropsychiatric symptoms across several disease entities. An improved understanding of these underlying mechanisms may help develop novel therapeutic targets in the form of drugs specifically targeting downstream products of TNF-α activation within the central nervous system.

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

“…High serum levels of TNF-α are associated with neuropsychiatric disorders such as major depressive disorder (11,54), abnormalities of brain development including autism (55), autoimmune diseases such as multiple sclerosis and rheumatoid arthritis (56), postoperative cognitive decline (57), and neurodegenerative diseases such as Alzheimer's disease (58). High serum cytokine levels in patients immunized with lipopolysaccharide or Salmonella typhi vaccination has been associated with cognitive changes including mental confusion (17) and depressive symptoms including psychomotor retardation (11,59). The potent effect of cytokines on cortical plasticity and cognition likely extends beyond EAE and may have wider implications in human disease.…”

“…The increased production of proinflammatory cytokines and infiltration of peripheral immune cells into the central nervous system (CNS) are closely associated with neuronal damage in the spinal cord and many brain regions (6)(7)(8)(9)(10). Elevation of several cytokines such as TNF-α and IFN-γ precedes infiltration of peripheral immune cells and could have a significant impact on neuronal function (11)(12)(13)(14)(15)(16)(17)(18)(19), potentially contributing to early sensory and cognitive impairments. However, the link between the cytokine elevation and CNS deficits in autoimmune diseases remains unclear.…”

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

“…Tumor necrosis factor (TNF)-a has an important role in the development and progression of cognitive decline, as well as depressive and anxiety disorders (Bai et al, 2013;Baune et al, 2012;Camara et al, 2013;Kaster et al, 2012). Indeed, peripheral inflammatory conditions like rheumatoid arthritis (RA) and psoriasis that show high levels of circulating TNF-a are associated with psychiatric symptoms, such as cognitive decline, anxiety, and depression (Bassukas et al, 2008;Chandarana et al, 1987;Menter et al, 2010).…”

TNFR1 absence protects against memory deficit induced by sepsis possibly through over-expression of hippocampal BDNF

“…As an increase in inflammatory cytokines was observed in TNFR1 KO in the absence of an overt memory deficit, they might have played a minor role in the cognitive performance in this model. The presence of TNFR1 would be associated with the development of memory impairment or, alternatively, the preferential stimulation of TNFR2 might have exerted neuroprotective effects in septic encephalopathy, possibly through the stimulation of the release of neurotrophins such as BDNF and neural growth factor (NGF) (Baune et al 2012;Camara et al 2013). A dual role for TNF-α receptors has already been established in an experimental autoimmune encephalitis model in which TNFR2 KO mice exhibited increased CNS lesions compared with TNFR1 KO mice (Suvannavejh et al 2000).…”