title: Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis.
abstract: BACKGROUND
  Inflammation is a key pathological hallmark of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and familial amyloidotic polyneuropathy (FAP). Among all inflammatory cytokines associated with FAP, IL-1β, in particular, has been implicated in playing a key pathogenic role. In the present study, we sought to investigate whether blocking IL-1β signaling provides disease-modifying benefits in an FAP mouse model.
  
  
  METHODS
  We assessed the effect of chronic administration of Anakinra, an IL-1 antagonist, on FAP pathogenesis in vivo, using real-time polymerase chain reaction (qPCR), semi-quantitative immunohistochemistry (SQ-IHC), western blot and nerve morphometric analyses.
  
  
  RESULTS
  We found that treatment with Anakinra prevents transthyretin (TTR) extracellular deposition in sciatic nerve, protecting unmyelinated nerve fibers from aggregate-induced degeneration. Moreover, Anakinra administration significantly suppressed IL-1 signaling pathway and inhibited apoptosis and nitrative stress.
  
  
  CONCLUSIONS
  The present work highlights the relevance of the IL-1 signaling pathway in the pathophysiology of FAP. Our results bring to light the importance of non-amyloid targets in the therapeutic strategies for this disorder. Thus, we propose the use of Anakinra as a potential therapeutic agent for TTR-related amyloidosis.
authors.affiliation: Department of Molecular Neurobiology, Institute for Molecular and Cell Biology, Rua do Campo Alegre , Porto , Portugal .
authors.forename: Nádia Pereira
authors.initials: NP
authors.lastname: Gonçalves
authors.forename: Paulo
authors.initials: P
authors.lastname: Vieira
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D007279:Injections, Subcutaneous; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012584:Sciatic Nerve / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D019076:Transgenes
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D011228:Prealbumin; D066329:Protein Aggregates
keywords: Anakinra; cytokines; familial amyloidotic polyneuropathy; neurodegeneration; neuroinflammation; peripheral nervous system