RESUMO
The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aß accumulation, that is, the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aß at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aß) in the transgenic mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aß at early stages (upper panel). Furthermore, in the AD brain the number of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aß accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathology.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Progressão da Doença , Técnica Direta de Fluorescência para Anticorpo , Hipocampo/patologia , Técnicas Imunoenzimáticas , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Recently, increased attention has been directed towards medicinal extracts as potential new drug candidates for dementia. Ginger has long been used as an important ingredient in cooking and traditional herbal medicine. In particular, ginger has been known to have disease-modifying effects in Alzheimer's disease (AD). However, there is no evidence of which constituents of ginger exhibit therapeutic effects against AD. A growing number of experimental studies suggest that 6-shogaol, a bioactive component of ginger, may play an important role as a memory-enhancing and anti-oxidant agent against neurological diseases. 6-Shogaol has also recently been shown to have anti-neuroinflammatory effects in lipopolysaccharide (LPS)-treated astrocytes and animal models of Parkinson's disease, LPS-induced inflammation and transient global ischemia. However, it is still unknown whether 6-shogaol has anti-inflammatory effects against oligomeric forms of the Aß (AßO) in animal brains. Furthermore, the effects of 6-shogaol against memory impairment in dementia models are also yet to be investigated. In this study, we found that administration of 6-shogaol significantly reduced microgliosis and astrogliosis in intrahippocampal AßO-injected mice, ameliorated AßO and scopolamine-induced memory impairment, and elevated NGF levels and pre- and post-synaptic marker in the hippocampus. All these results suggest that 6-shogaol may play a role in inhibiting glial cell activation and reducing memory impairment in animal models of dementia.
Assuntos
Catecóis/administração & dosagem , Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , Encefalite/tratamento farmacológico , Animais , Cognição/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Demência/complicações , Demência/fisiopatologia , Relação Dose-Resposta a Droga , Encefalite/complicações , Encefalite/fisiopatologia , Zingiber officinale/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/administração & dosagem , Extratos Vegetais/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Focal cortical dysplasias (FCDs) are a heterogenous cluster of histopathologic entities classically associated with medically refractory epilepsy. Because there is substantial histopathologic variation among different types of FCD, there are likely multiple pathogenic mechanisms leading to these disorders. The meninges are known to play a role in cortical development, and disruption of meningeal-derived signaling pathways has been shown to impact neurodevelopment. To our knowledge, there has not yet been an investigation into whether genetic pathways regulating meningeal development may be involved in the development of FCD. OBSERVATIONS: The authors reported a patient with refractory epilepsy and evidence of FCD on imaging who received surgical intervention and was found to have an unusual dural anomaly overlying a region of type Ic FCD. To the authors' knowledge, this was the first report describing a lesion of this nature in the context of FCD. LESSONS: The dural anomaly exhibited by the patient presented what could be a potentially novel pathogenic mechanism of FCD. Resection of the cortical tissue underlying the dural anomaly resulted in improvement in seizure control. Although the pathogenesis is unclear, this case highlighted the importance of further investigation into the developmental origins of FCD, which may help elucidate whether a connection between meningeal development and FCD exists.
Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encefalomielite/diagnóstico por imagem , Meningite/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Idoso , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/imunologia , Encefalomielite/tratamento farmacológico , Encefalomielite/imunologia , Feminino , Proteína Glial Fibrilar Ácida/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Meningite/tratamento farmacológico , Meningite/imunologia , Metilprednisolona/uso terapêuticoRESUMO
Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy.