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

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...

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Bibliographic Details
Published in:Molecular neurobiology 2019-03, Vol.56 (3), p.1539-1557
Main Authors: Remor, Aline Pertile, da Silva, Rodrigo Augusto, de Matos, Filipe José, Glaser, Viviane, de Paula Martins, Roberta, Ghisoni, Karina, da Luz Scheffer, Débora, Andia, Denise Carleto, Portinho, Daniele, de Souza, Ana Paula, de Oliveira, Paulo Alexandre, Prediger, Rui Daniel, Torres, Alicia I., Linhares, Rose Marie Mueller, Walz, Roger, Ronsoni, Marcelo Fernando, Hohl, Alexandre, Rafacho, Alex, Aguiar, Aderbal Silva, De Paul, Ana Lucia, Latini, Alexandra
Format: Article
Language:English
Subjects:
Adipose tissue
Adolescents
Anthropometry
Ascorbic acid
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cell survival
Children
Cognitive ability
Dementia disorders
Demethylation
Deoxyribonucleic acid
DNA
Epigenetics
Health risks
Hippocampus
Homeostasis
Hyperglycemia
Inactivation
Leukocytes (mononuclear)
Metabolism
Neurobiology
Neurodegenerative diseases
Neurology
Neuroprotection
Neurosciences
Neurotoxicity
Obesity
Oxidative stress
Peripheral blood mononuclear cells
Risk factors
Streptozocin
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Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-018-1175-9