RESUMO
Chronic neuroinflammatory processes including glial activation may play a role in the pathogenesis of Alzheimer's disease (AD). The immune and inflammatory mediator CD40 ligand (CD40L) can augment the activation of cultured microglia by amyloid beta-protein (Abeta) and promote neuron death. We investigated whether CD40L is increased in AD and in animal models of AD and neuroinflammation. In the frontal cortex of elderly, non-AD controls, CD40L immunoreactivity was found in the glial limiting membrane, astrocytes, and vascular profiles in gray and white matter. In AD, intense CD40L immunoreactivity occurred in hypertrophied astrocytes throughout the frontal cortex. The majority of CD40L-immunoreactive astrocytes in the gray matter occurred within, or at the periphery of, Abeta(1-42)-immunoreactive plaques. A semiquantitative analysis revealed a three-fold elevation in the number of CD40L-immunoreactive astrocytes in AD compared to controls. The cortex and hippocampus from 6 and 12 month-old amyloid precursor protein/presenilin 1 transgenic mice exhibited numerous neuritic plaques and CD40L-positive astrocytes, which were not detected in non-transgenic controls. In adult rats, little or no CD40L staining occurred in astrocytes of the intact brain, whereas intrastriatal excitotoxic or stab wound lesions produced a strong CD40L immunoreactivity that was more segregated than glial fibrillary acidic protein. These findings indicate that astrocytes are the predominant source of CD40L in brain, and are consistent with the proposed role of CD40L-mediated neurotoxic inflammation in AD.
Assuntos
Doença de Alzheimer/metabolismo , Lesões Encefálicas/metabolismo , Ligante de CD40/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Animais , Antígenos CD40/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Ácido Quinolínico/farmacologia , Ratos , Ratos WistarRESUMO
The regulator of G protein signaling (RGS) molecules are a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G protein signaling 4 (RGS4) is of particular interest in schizophrenia since it is associated with the dopamine (DA) receptor, its expression is altered in affected CNS tissue, and polymorphisms in the RGS4 gene are being examined as risk factors for the disease (Morris et al.2004, Am J Med Genet B Neuropsychiatr Genet 125:50-53; Prasad et al.2005, Mol Psychiatry 10:213-219; Williams et al.2004, Biol Psychiatry 55:192-195). To further test for the involvement of RGS4 expression in schizophrenia, we examined a selection of different cortical and subcortical regions in human brain for alterations in RGS4 mRNA and protein expression. To evaluate the effect of antipsychotic medication on RGS4 expression levels, we compared a subset of treated and untreated cases that were off antipsychotic medication for at least 3 months prior to death. We report a significant decrease in RGS4 mRNA levels in the cingulate gyrus, superior frontal gyrus, and the insular cortex of all schizophrenia cases when compared with controls. A decrease in RGS4 mRNA was also observed in the caudate, but only in the medicated schizophrenia cases. Measurement of protein levels using Western blot demonstrated that RGS4 protein is decreased in the frontal cortex of schizophrenia cases.
Assuntos
Encéfalo/metabolismo , Proteínas RGS/biossíntese , Esquizofrenia/metabolismo , Adulto , Antipsicóticos/uso terapêutico , Autorradiografia , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologiaRESUMO
Regulators of G-protein signalling (RGS) proteins are a recently discovered class of proteins that modulate G-protein activity. More than 20 RGS proteins have been identified and are expressed throughout the body and brain. In particular, RGS4 appears to regulate dopamine receptor function and has been implicated in several dopamine related diseases, including schizophrenia. This study presents an extensive examination of the regional distribution of RGS4 mRNA in postmortem human brain. Using in situ hybridization, the expression levels of RGS4 mRNA were determined in human hemicoronal (Talairach sections +8 and -20) brain sections. In the rostral slice (Talairach +8) highest levels were found in the inferior frontal cortex, the superior frontal, and the cingulate cortex. Slightly lower levels were found in the insular cortex and inferior temporal cortex. The caudate, putamen and nucleus accumbens had lower levels. In the caudal slice (-20), the cortical layers showed the highest levels, with moderate levels observed in the parahippocampal gyrus, low levels in the CA-pyramidal region, and almost undetectable levels in the thalamus. In the frontal cortex a dense band was apparent near one of the inner layers of the cortex. In conclusion, RGS4 mRNA distribution in human postmortem tissue from normal persons was very dense in most cortical layers examined, with lower density in the basal ganglia and thalamus.