| Autor: |
Yonamine CY; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Passarelli M; Laboratório de Lipides (LIM-10) do HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, Brazil.; Programa de Pos-Graduação em Medicina, Universidade Nove de Julho (UNINOVE), São Paulo 01525-000, Brazil., Suemoto CK; Divisao de Geriatria, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil., Pasqualucci CA; Departamento de Patologia, Universidade de Sao Paulo, São Paulo 01246-000, Brazil., Jacob-Filho W; Divisao de Geriatria, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil., Alves VAF; Laboratório de Investigação Médica em Patologia Hepática, (LIM14) do Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246-000, Brazil., Marie SKN; Departamento de Neurologia, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil., Correa-Giannella ML; Laboratorio de Carboidratos e Radioimunoensaio (LIM-18) do Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01246-000, Brazil., Britto LR; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil., Machado UF; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil. |
| Abstrakt: |
Diabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4 /GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1 , TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4 /GLUT4 expression but also the expression of some genes related to neuronal function ( SYN1 , TH , SYP ). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration. |
