RESUMO
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.
Assuntos
Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/metabolismo , Sintomas Comportamentais/etiologia , Índice Glicêmico , Animais , Transtorno do Espectro Autista/genética , Proteína C-Reativa/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/etiologia , Asseio Animal/fisiologia , Proteínas de Arcabouço Homer , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Relações Interpessoais , Aprendizagem em Labirinto/classificação , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeos/metabolismo , Oxirredutases/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismoRESUMO
The role of the Bax gene product was examined in three forms of cortical nerve cell death in primary cultures. These include spontaneous cell death, oxidative glutamate toxicity, in which exogenous glutamate inhibits cystine uptake resulting in toxic oxidative stress, and ionotropic glutamate receptor-mediated excitotoxicity following a brief exposure to 10 microM glutamate. Primary cortical and hippocampal neuron cultures were established from embryos of Bax -/+ x Bax -/+ matings and the embryos genotyped and assayed for cell death in the three experimental paradigms. Cell death induced by oxidative glutamate toxicity and glutamate-mediated excitotoxicity was not altered in the Bax -/- homozygous knockout animals. In contrast, there was an approximately 50% inhibition of spontaneous cell death. These results suggest that a classical Bax-dependent apoptotic pathway contributes to the spontaneous cell death that takes place when nerve cells are initially exposed to cell culture conditions. A Bax-dependent programmed cell death pathway is not, however, utilized in oxidative glutamate toxicity and NMDA receptor-mediated excitotoxicity following a brief exposure to low concentrations of glutamate.
Assuntos
Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/metabolismo , Animais , Apoptose/genética , Morte Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Ácido Glutâmico/farmacologia , Heterozigoto , Homozigoto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neurônios/citologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estaurosporina/farmacologia , Proteína X Associada a bcl-2RESUMO
Approximately 50% of familial Alzheimer's disease (AD) cases are linked to the presenilin (PS) gene. This suggests that an altered function of mutated PSs accounts for a fundamental process leading to AD. Here we identify a new PS binding protein, PBP, which is highly expressed in cerebral cortex and hippocampus. immunohistochemical studies and cell fractionation analysis show that PBP redistributes from cytoplasm to membranes in the presence of PS. In addition, PBP is deficient in the soluble fraction of sporadic AD brains.
Assuntos
Proteínas de Transporte/análise , Fatores de Troca do Nucleotídeo Guanina , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Animais , Northern Blotting , Western Blotting , Células COS , Proteínas de Transporte/química , Proteínas de Transporte/genética , Fracionamento Celular , Linhagem Celular , Membrana Celular/química , Córtex Cerebral/química , Córtex Cerebral/ultraestrutura , Citoplasma/química , DNA Complementar , Hipocampo/química , Hipocampo/ultraestrutura , Humanos , Imuno-Histoquímica , Hibridização In Situ , Rim , Camundongos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Presenilina-1 , Saccharomyces cerevisiae , TransfecçãoRESUMO
Oxidative stress is implicated in several pathologies such as AIDS, Alzheimer's disease, and Parkinson's disease, as well as in normal aging. As a model system to study the response of cells to oxidative insults, glutamate toxicity on a mouse nerve cell line, HT-22, was examined. Glutamate exposure kills HT-22 via a nonreceptor-mediated oxidative pathway by blocking cystine uptake and causing depletion of intracellular glutathione (GSH), leading to the accumulation of reactive oxygen species and, ultimately, apoptotic cell death. Several HT-22 subclones that are 10-fold resistant to exogenous glutamate were isolated and the mechanisms involved in resistance characterized. The expression levels of neither heat shock proteins nor apoptosis-related proteins are changed in the resistant cells. In contrast, the antioxidant enzyme catalase, but not glutathione peroxidase nor superoxide dismutase, is more highly expressed in the resistant than in the parental cells. In addition, the resistant cells have enhanced rates of GSH regeneration due to higher activities of the GSH metabolic enzymes gamma-glutamylcysteine synthetase and GSH reductase, and GSH S-transferases activities are also elevated. As a consequence of these alterations, the glutamate resistant cells are also more resistant to organic hydroperoxides and anticancer drugs that affect these GSH enzymes. These results indicate that resistance to apoptotic oxidative stress may be acquired by coordinated changes in multiple antioxidant pathways.
Assuntos
Sobrevivência Celular/fisiologia , Estresse Oxidativo/fisiologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Antioxidantes/metabolismo , Transporte Biológico , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cistationina/metabolismo , Cistina/metabolismo , Resistência a Medicamentos , Glutamato-Cisteína Ligase/metabolismo , Ácido Glutâmico/farmacologia , Glutationa/metabolismo , Proteínas de Choque Térmico/análise , Homocisteína/análogos & derivados , Homocisteína/farmacologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/genética , Oxirredutases/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Tempo , Regulação para Cima/genética , Proteína X Associada a bcl-2RESUMO
It has been suggested that a receptor for advanced glycation end products (RAGE) is the nerve cell receptor for amyloid beta protein (A beta). To determine if this is indeed the case, two neural cell lines as well as rat cortical neurons were examined for the presence of the mRNA for RAGE by PCR and northern blot analysis. Although lung was strongly positive, in no case was RAGE mRNA detected in the cultured neural cells. Glycated-albumin is a major ligand for RAGE and the cell surface RAGE protein is trypsin sensitive. In agreement with the mRNA data, trypsin treatment did not alter A beta toxicity, nor did glycated albumin modify the A beta response. It follows that RAGE is not the neural receptor for A beta.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Neurônios/fisiologia , Receptores Imunológicos/biossíntese , Animais , Northern Blotting , Neoplasias Encefálicas , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células PC12/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Reação em Cadeia da Polimerase , Ratos , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/fisiologia , Soroalbumina Bovina/farmacologia , Tripsina/farmacologia , Células Tumorais CultivadasRESUMO
Clones of the rat pheochromocytoma cell line PC12 were selected for their resistance to amyloid beta protein (A beta). These A beta-resistant cells also survive higher concentrations of exogenously applied peroxides than the parent cells. A beta triggers intracellular H2O2 accumulation in the parent PC12 cells but not in the A beta-resistant cells. The absence of H2O2 accumulation in A beta-resistant cells is not attributable to differences in A beta binding to the cell surface. However, the mRNA and protein levels of catalase and glutathione peroxidase, as well as the corresponding enzyme activities, are highly elevated in A beta-resistant clones. These activities correlate well with the increased resistance of cells to A beta or peroxides. Finally, cells transfected with catalase and glutathione peroxidase are also more resistant to A beta toxicity. These results indicate that increased antioxidant enzyme activities in A beta-resistant cells account for at least part of their resistance to A beta and substantiate further the role of H2O2 in A beta toxicity.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Antioxidantes/metabolismo , Células PC12/enzimologia , Doença de Alzheimer/enzimologia , Animais , Catalase/metabolismo , Células Cultivadas , Glutationa Peroxidase/metabolismo , Microscopia Eletrônica , Células PC12/ultraestrutura , RatosRESUMO
beta-Amyloid protein (A beta) is a member of a small group of proteins that accumulate as amyloid deposits in various tissues. It has recently been demonstrated that the toxicity of A beta toward some neural cells is caused by oxidative damage. Since all of the amyloid diseases are characterized by protein deposited in the antiparallel beta-sheet conformation, it was asked whether there is a common toxic mechanism. It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells. The toxicity is mediated via a free radical pathway indistinguishable from that of A beta. Experiments with synthetic peptides suggest that it is the amphiphilic nature of the peptides generated by their beta structure rather than their beta structure per se that causes toxicity. These results tend to rule out the alternative that amyloid toxicity is exclusively mediated via specific cell surface receptors.