RESUMO
Alzheimer's disease (AD) patients tend to have increased plasma levels of homocysteine. However, it is unclear whether abnormality in homocysteine levels is a primary cause of Alzheimer's disease or a disease marker. In order to investigate the relative impact of Alzheimer's disease on plasma homocysteine levels, total plasma homocysteine levels were evaluated in transgenic mouse models that exhibit abnormalities in their brains that are similar to Alzheimer's patients. No significant difference was observed in blood of murine models compared to control mice, indicating that elevated plasma homocysteine level seems to be a risk marker at the most.
Assuntos
Doença de Alzheimer/sangue , Homocisteína/sangue , Animais , Biomarcadores , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Fatores de RiscoAssuntos
Betacoronavirus , Pesquisa Biomédica/organização & administração , Infecções por Coronavirus/prevenção & controle , Oftalmologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Academias e Institutos/organização & administração , COVID-19 , França , Humanos , SARS-CoV-2 , Local de Trabalho/organização & administraçãoRESUMO
FE65 is an adaptor protein that interacts with the cytoplasmic tail of the amyloid precursor protein (APP). In cultured non-neuronal cells, the formation of the FE65-APP complex is a key element for the modulation of APP processing, signalling and beta-amyloid (Abeta) production. The functions of FE65 in vivo, including its role in the metabolism of neuronal APP, remain to be investigated. In this study, transgenic mice expressing human FE65 were generated and crossbred with APP transgenic mice, known to develop Abeta deposits at 6 months of age. Compared with APP mice, APP/FE65 double transgenic mice exhibited a lower Abeta accumulation in the cerebral cortex as demonstrated by immunohistochemistry and immunoassay, and a lower level of APP-CTFs. The reduced accumulation of Abeta in APP/FE65 double transgenics, compared with APP mice, could be linked to the low Abeta42 level observed at 4 months of age and to the lower APP-CTFs levels. The present work provides evidence that FE65 plays a role in the regulation of APP processing in an in vivo model.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas Nucleares/biossíntese , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Processamento de Proteína Pós-Traducional/genéticaRESUMO
Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases. Various neuronal diseases have been associated with hyperhomocysteinemia, but the molecular mechanisms of homocysteine toxicity are unknown. We investigated the pathways involved in the pathological process, by analyzing differential gene expression in neuronal tissues. We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both plasma and brain homocysteine concentrations were high. Several genes were found to be differentially expressed in the brains of CBS-deficient mice, and the identities of some of these genes suggested that the SAPK/JNK pathway was altered in the brains of CBS-deficient mice. We therefore investigated the activation of proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway may play an important role in the development of neuronal defects associated with hyperhomocysteinemia.
Assuntos
Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , MAP Quinase Quinase 4 , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Fator 2 Ativador da Transcrição , Animais , Encéfalo/citologia , Química Encefálica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Homocisteína/sangue , Homocisteína/metabolismo , Hiper-Homocisteinemia/genética , Proteínas Quinases JNK Ativadas por Mitógeno , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.