Extracellular Vesicles from Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats.

Autores de INCLIVA

• Andrea Cabrera Pastor

  Autor

• 

  María Del Carmen Montoliu Félix

  Autor

Participantes ajenos a INCLIVA

• Izquierdo-Altarejos, Paula
• Gonzalez-King, Hernan
• Felipo, Vicente

Grupos y Plataformas de I+D+i

• Grupo de Investigación de Deterioro Neurológico

  

  Leading Researcher

  María Del Carmen Montoliu Félix

Abstract

Minimal hepatic encephalopathy is associated with changes in the peripheral immune system which are transferred to the brain, leading to neuroinflammation and thus to cognitive and motor impairment. Mechanisms by which changes in the immune system induce cerebral alterations remain unclear. Extracellular vesicles (EVs) seem to play a role in this process in certain pathologies. The aim of this work was to assess whether EVs play a role in the induction of neuroinflammation in cerebellum and motor incoordination by chronic hyperammonemia. We characterized the differences in protein cargo of EVs from plasma of hyperammonemic and control rats by proteomics and Western blot. We assessed whether injection of EVs from hyperammonemic to normal rats induces changes in neuroinflammation in cerebellum and motor incoordination similar to those exhibited by hyperammonemic rats. We found that hyperammonemia increases EVs amount and alters their protein cargo. Differentially expressed proteins are mainly associated with immune system processes. Injected EVs enter Purkinje neurons and microglia. Injection of EVs from hyperammonemic, but not from control rats, induces motor incoordination, which is mediated by neuroinflammation, microglia and astrocytes activation and increased IL-1b, TNFalpha, its receptor TNFR1, NF-kB in microglia, glutaminase I, and GAT3 in cerebellum. Plasma EVs from hyperammonemic rats carry molecules necessary and sufficient to trigger neuroinflammation in cerebellum and the mechanisms leading to motor incoordination.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Keywords

• hepatic encephalopathy; TNF alpha; TNF alpha receptor TNFR1; glial activation