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Chronic Metabolic Derangement-Induced Cognitive Deficits and Neurotoxicity Are Associated with REST Inactivation

  • Aline Pertile Remor
  • Rodrigo Augusto da Silva
  • Filipe José de Matos
  • Viviane Glaser
  • Roberta de Paula Martins
  • Karina Ghisoni
  • Débora da Luz Scheffer
  • Denise Carleto Andia
  • Daniele Portinho
  • Ana Paula de Souza
  • Paulo Alexandre de Oliveira
  • Rui Daniel Prediger
  • Alicia I. Torres
  • Rose Marie Mueller Linhares
  • Roger Walz
  • Marcelo Fernando Ronsoni
  • Alexandre Hohl
  • Alex Rafacho
  • Aderbal Silva AguiarJr
  • Ana Lucia De Paul
  • Alexandra Latini
Article

Abstract

Chronic metabolic alterations may represent a risk factor for the development of cognitive impairment, dementia, or neurodegenerative diseases. Hyperglycemia and obesity are known to imprint epigenetic markers that compromise the proper expression of cell survival genes. Here, we showed that chronic hyperglycemia (60 days) induced by a single intraperitoneal injection of streptozotocin compromised cognition by reducing hippocampal ERK signaling and by inducing neurotoxicity in rats. The mechanisms appear to be linked to reduced active DNA demethylation and diminished expression of the neuroprotective transcription factor REST. The impact of the relationship between adiposity and DNA hypermethylation on REST expression was also demonstrated in peripheral blood mononuclear cells in obese children with reduced levels of blood ascorbate. The reversible nature of epigenetic modifications and the cognitive impairment reported in obese children, adolescents, and adults suggest that the correction of the anthropometry and the peripheral metabolic alterations would protect brain homeostasis and reduce the risk of developing neurodegenerative diseases.

Keywords

Mitochondrial dysfunction Inflammation and oxidative stress Hyperglycemia Cognitive deficit DNA methylation 

Notes

Acknowledgments

The authors are grateful to Theodore Griswold for language editing.

Author Contributions

A.P.R. designed, planned, and performed the animal model; carried out biochemical measurements, Western blot assays, and data analyses; prepared the initial figures; and revised the manuscript. R.A.S. designed and performed the animal model; carried out molecular assays, epigenetic measurements, and data analyses; and revised the manuscript. F.J.M. set up the animal model and performed the PCR assays; V.G. carried out histochemical and PCR analyses; R.D.P performed Western blot assays and HPLC measurements; D.L.S., D.P., and D.C.A. performed DNA studies and data analyses; A.R. coordinated insulin-related Western blot studies and insulin measurements; P.A.O. performed behavioral tests; M.F.R., A.H., R.M.M.L., and R.W. were responsible for the clinical data from obese and diabetic patients, collected the samples, and were responsible for funding acquisition; R.D.P. coordinated the behavioral tests and revised the manuscript; A.P.S. performed the DNA extraction and revised the manuscript; A.S.A.Jr. performed statistics, revised the manuscript, and was responsible for funding acquisition; A.T. and A.L.D.P. performed the immunoelectron microscopy assays and was responsible for funding acquisition; A.L. coordinated all experimental procedures and data analyses, prepared the final version of the figures, wrote the manuscript, was responsible for funding acquisition, and provided the required infrastructure.

Funding Information

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (479222/2013-4); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (PVE: 004_2013 and 88881.062164/2014-01, INCT 189405 16/2014); Programa de Apoio a Núcleos de Excelência PRONEX (NENASC Project); Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba, Argentina; Fondo para la Investigación Científica y Tecnológica, Argentina; and Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. R.D.P., A.S.A.Jr., R.W. and A.L. are CNPq fellows.

Compliance with Ethical Standards

All procedures detailed in this study employing experimental animals were performed under the ethical guidelines of the Ethics Committee for Animal Research (PP00350/CEUA) of the Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil, and were carried out in accordance with the ARRIVE guidelines. All the human experiments were performed under the ethical guidelines of the Ethics Committee for Human Research (CEPSH/435/09, CEPSH/2150/2011, and CAAE 33173314.7.0000.0121) of the Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil, and subjects’ consent was obtained according to the Declaration of Helsinki.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Aline Pertile Remor
    • 1
    • 2
  • Rodrigo Augusto da Silva
    • 1
    • 3
  • Filipe José de Matos
    • 1
  • Viviane Glaser
    • 1
  • Roberta de Paula Martins
    • 1
  • Karina Ghisoni
    • 1
  • Débora da Luz Scheffer
    • 1
  • Denise Carleto Andia
    • 4
  • Daniele Portinho
    • 3
  • Ana Paula de Souza
    • 3
  • Paulo Alexandre de Oliveira
    • 5
  • Rui Daniel Prediger
    • 5
  • Alicia I. Torres
    • 6
    • 7
  • Rose Marie Mueller Linhares
    • 8
    • 9
  • Roger Walz
    • 10
  • Marcelo Fernando Ronsoni
    • 11
  • Alexandre Hohl
    • 11
  • Alex Rafacho
    • 12
  • Aderbal Silva AguiarJr
    • 1
  • Ana Lucia De Paul
    • 6
    • 7
  • Alexandra Latini
    • 1
    • 13
  1. 1.Laboratório de Bioenergética e Estresse Oxidativo (LABOX), Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa Catarina (UFSC)FlorianópolisBrazil
  2. 2.Programa de Pós-Graduação em Biociências e Saúde, Área de Ciências da VidaUniversidade do Oeste de Santa CatarinaJoaçabaBrazil
  3. 3.Laboratório de Biologia Molecular, Departamento de Morfologia, Faculdade de Odontologia de PiracicabaUniversidade Estadual de São PauloPiracicabaBrazil
  4. 4.Faculdade de Odontologia, Área de Pesquisa em EpigenéticaUniversidade Paulista, UNIPSão PauloBrazil
  5. 5.Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Centro de Ciências BiológicasUFSCFlorianópolisBrazil
  6. 6.Centro de Microscopía Electrónica, Facultad de Ciencias MédicasUniversidad Nacional de CórdobaCórdobaArgentina
  7. 7.Consejo Nacional de Investigaciones Cietificas y Técnicas (CONICET)Instituto de Investigaciones en Ciencias de la Salud (INICSA)CórdobaArgentina
  8. 8.Hospital Universitário, Serviço de Endocrinologia Pediátrica, Departamento de PediatriaUFSCFlorianópolisBrazil
  9. 9.Hospital Infantil Joana de GusmãoFlorianópolisBrazil
  10. 10.Centro de Neurociências Aplicadas (CeNap), Departamento de Clínica Médica, Hospital UniversitárioUFSCFlorianópolisBrazil
  11. 11.Hospital Universitário, Serviço de Endocrinologia e Metabologia, Departamento de Clínica MédicaUFSCFlorianópolisBrazil
  12. 12.Laboratório de Investigação de Doenças Crônicas, Departamento de Fisiologia, Centro de Ciências BiológicasUFSCFlorianópolisBrazil
  13. 13.Harvard Medical School, Boston Children’s Hospital, Center for Life SciencesHarvard UniversityBostonUSA

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