The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involvement as well as cellular activation with subsequent proliferation and programmed cell death or necrosis. As might be expected with such a broad spectrum of cellular effects and complex signalling pathways, TNF has also been implicated in a number of disease states, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Since the time of its discovery over 40 years ago, TNF ligand and its receptors, TNF receptor (TNFR) 1 and 2, have been categorised into two complementary superfamilies, namely TNF (TNFSF) and TNFR (TNFRSF), and 19 ligands and 29 receptors have been identified to date. There have been significant advances in our understanding of TNF signalling pathways in the last decade, and this short review aims to elucidate some of the most recent advances involving TNF signalling in health and disease.

Several different receptor proteins have been identified that bind monomeric, oligomeric, or fibrillar forms of amyloid-β (Aβ). “Good” receptors internalize Aβ or promote its transcytosis out of the brain, whereas “bad” receptors bind oligomeric forms of Aβ that are largely responsible for the synapticloss, memory impairments, and neurotoxicity that underlie Alzheimer disease. The prion protein both removes Aβ from the brain and transduces the toxic actions of Aβ. The clustering of distinct receptors in cell surface signaling platforms likely underlies the actions of distinct oligomeric species of Aβ. These Aβ receptor-signaling platforms provide opportunities for therapeutic intervention in Alzheimer disease.

IntroductionSynapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt–planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death.MethodsWe compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway.ResultsWe demonstrate that Aβ synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil.DiscussionOur data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease.

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.