Original Research ARTICLE
Soluble fibrinogen triggers non-cell autonomous ER stress-mediated microglial-induced neurotoxicity
- 1Institute of Neurology, University College London, United Kingdom
- 2Institute of Neurology, University College London, United Kingdom
Aberrant or chronic microglial activation is strongly implicated in neurodegeneration, where prolonged induction of classical inflammatory pathways may lead to a compromised blood-brain barrier (BBB) or vasculature, features of many neurodegenerative disorders and implicated in the observed cognitive decline. BBB disruption or vascular disease may expose the brain parenchyma to ‘foreign’ plasma proteins which subsequently impact on neuronal network integrity through neurotoxicity, synaptic loss and the potentiation of inflammation. Here we show that the blood coagulation factor fibrinogen (FG), implicated in the pathogenesis of dementias such as Alzheimer’s disease (AD), induces an inflammatory microglial phenotype as identified through genetic microarray analysis of a microglial cell line, and cytokine profiling of primary microglia. We also identify a FG-mediated induction of non-cell autonomous ER stress-associated neurotoxicity via an inflammatory pathway that can be blocked by pharmacological inhibition of microglial TNFα transcription or neuronal caspase-12 activity, supporting a disease relevant role for plasma components in neuronal dysfunction.
Keywords: Neurodegenaration, Alzheime´s Disease, er stress, Fibrinogen, Microglia
Received: 03 Sep 2018;
Accepted: 19 Oct 2018.
Edited by:Liliana Bernardino, Universidade da Beira Interior, Portugal
Reviewed by:Marta Fumagalli, Università degli Studi di Milano, Italy
Gordon Meares, West Virginia University, United States
Copyright: © 2018 Piers, East, Villegas-Llerena, Sevastou, Matarin, Hardy and Pocock. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: PhD. Jennifer M. Pocock, University College London, Institute of Neurology, London, WC1E 6BT, United Kingdom, firstname.lastname@example.org