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

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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.

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Acknowledgments

The authors are grateful to Theodore Griswold for language editing.

Funding

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.

Author information

Author notes

  1. Aline Pertile Remor and Rodrigo Augusto da Silva contributed equally to this work.

Authors and Affiliations

  1. Laboratório de Bioenergética e Estresse Oxidativo (LABOX), Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário – Córrego Grande, Bloco C 201/214, Florianópolis, SC, 88040-900, Brazil

    Aline Pertile Remor, Rodrigo Augusto da Silva, Filipe José de Matos, Viviane Glaser, Roberta de Paula Martins, Karina Ghisoni, Débora da Luz Scheffer, Aderbal Silva Aguiar Jr & Alexandra Latini

  2. Programa de Pós-Graduação em Biociências e Saúde, Área de Ciências da Vida, Universidade do Oeste de Santa Catarina, Joaçaba, 89600-000, Brazil

    Aline Pertile Remor

  3. Laboratório de Biologia Molecular, Departamento de Morfologia, Faculdade de Odontologia de Piracicaba, Universidade Estadual de São Paulo, Piracicaba, SP, 13414-903, Brazil

    Rodrigo Augusto da Silva, Daniele Portinho & Ana Paula de Souza

  4. Faculdade de Odontologia, Área de Pesquisa em Epigenética, Universidade Paulista, UNIP, São Paulo, SP, 04026-002, Brazil

    Denise Carleto Andia

  5. Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Centro de Ciências Biológicas, UFSC, Florianópolis, SC, 88040-900, Brazil

    Paulo Alexandre de Oliveira & Rui Daniel Prediger

  6. Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, 5000, Córdoba, Argentina

    Alicia I. Torres & Ana Lucia De Paul

  7. Consejo Nacional de Investigaciones Cietificas y Técnicas (CONICET), Instituto de Investigaciones en Ciencias de la Salud (INICSA), 5000, Córdoba, Argentina

    Alicia I. Torres & Ana Lucia De Paul

  8. Hospital Universitário, Serviço de Endocrinologia Pediátrica, Departamento de Pediatria, UFSC, Florianópolis, SC, 88040-900, Brazil

    Rose Marie Mueller Linhares

  9. Hospital Infantil Joana de Gusmão, Florianópolis, SC, 88025-301, Brazil

    Rose Marie Mueller Linhares

  10. Centro de Neurociências Aplicadas (CeNap), Departamento de Clínica Médica, Hospital Universitário, UFSC, Florianópolis, SC, 88040-900, Brazil

    Roger Walz

  11. Hospital Universitário, Serviço de Endocrinologia e Metabologia, Departamento de Clínica Médica, UFSC, Florianópolis, SC, 88040-900, Brazil

    Marcelo Fernando Ronsoni & Alexandre Hohl

  12. Laboratório de Investigação de Doenças Crônicas, Departamento de Fisiologia, Centro de Ciências Biológicas, UFSC, Florianópolis, SC, 88040-900, Brazil

    Alex Rafacho

  13. Harvard Medical School, Boston Children’s Hospital, Center for Life Sciences, Harvard University, Boston, MA, 02118, USA

    Alexandra Latini

Authors
  1. Aline Pertile Remor
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  2. Rodrigo Augusto da Silva
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  3. Filipe José de Matos
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  8. Denise Carleto Andia
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  9. Daniele Portinho
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  10. Ana Paula de Souza
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  11. Paulo Alexandre de Oliveira
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  12. Rui Daniel Prediger
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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.

Corresponding author

Correspondence to Alexandra Latini.

Ethics declarations

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.

Additional information

Highlights

• Impaired cognition and hippocampal ERK signaling were induced in hyperglycemic rats.

• Chronic metabolic disturbances elicited neurotoxicity with signs of neurodegeneration.

• Hyperglycemia elicited reduced hippocampal DNA demethylation with REST inactivation.

• Leukocytes from obese children showed repressed REST and DNA hypermethylation.

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Remor, A.P., da Silva, R.A., de Matos, F.J. et al. Chronic Metabolic Derangement-Induced Cognitive Deficits and Neurotoxicity Are Associated with REST Inactivation. Mol Neurobiol 56, 1539–1557 (2019). https://doi.org/10.1007/s12035-018-1175-9

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  • DOI: https://doi.org/10.1007/s12035-018-1175-9

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