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The Role of Secretase Pathway in Long-term Brain Inflammation and Cognitive Impairment in an Animal Model of Severe Sepsis

  • Cleonice Michelon
  • Monique Michels
  • Mariane Abatti
  • Andriele Vieira
  • Heloisa Borges
  • Diogo Dominguini
  • Tatiana Barichello
  • Felipe Dal-PizzolEmail author
Article

Abstract

Inflammatory cytokines are related to impaired learning and memory processes in the central nervous system, contributing to the cognitive dysfunction present in sepsis survivors. In sepsis, brain of survivors presented increased deposition of amyloid-beta (Aβ) peptide and this was associated with cognitive impairment. However, it is not known if the upregulation of secretase pathway is involved the deposition of Aβ peptide and consequent development of cognitive impairment in survivors. The aim of the study is to evaluate the effects of secretase inhibitors on behavioral, Aβ accumulation, and neuroinflammatory parameters in rats submitted to sepsis. Sepsis was induced by cecal ligation and perforation in Wistar rats, and the activity of alpha-, beta-, and gamma-secretases was determined in the hippocampus and prefrontal at different times. Additionally, in a different cohort of animal’s epigallocatechin gallate, a beta-secretase inhibitor or a gamma-secretase inhibitor was administrated once a day for three consecutive days. Fifteen or 30 days after sepsis induction, Aβ content, TNF-α, IL-1β, and IL-6 and cognitive performance were determined. There was no increase in alpha-secretase activity. Both beta- and gamma-secretase activities increased, mainly late after sepsis. The inhibition of beta- or gamma-secretases improved cognitive performance 10 days after sepsis induction, and beta-secretase inhibition improved cognitive performance up to 30 days after sepsis induction. Furthermore, beta-secretase inhibition decreased IL-1β and Aβ brain levels. It was demonstrated that during sepsis development there was an increase in the amyloidogenic route, and the inhibition of this pathway promoted attenuation of neuroinflammation, Aβ peptide content, and improvement of cognitive impairment.

Keywords

Amyloid-beta; Secretase pathway Inflammation Sepsis 

Notes

Funding Information

This work was supported by CAPES-001, FAPESC, CNPQ and UNESC.

Compliance with Ethical Standards

The experimental procedures involving animals were performed in accordance with the National Institutes of Health (Bethesda, MD, USA) Guide for Care and Use of Laboratory Animals and with the approval of our institutional ethics committee. Protocol number: 041/2016-1.

Conflicts of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Experimental Pathophysiology, Graduate Program in Health SciencesUniversity of Southern Santa CatarinaCriciúmaBrazil
  2. 2.Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA

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