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1.
J Neuropathol Exp Neurol ; 76(9): 769-778, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859334

RESUMO

Nonmotor neuron-related pathology is a feature of amyotrophic lateral sclerosis (ALS), both in patients and in animal models. There is emerging evidence that sensory systems (olfaction and vision) are affected in humans. Here, we asked whether such sensory neuropathology is recapitulated in the superoxide dismutase 1 (SOD1G93A) mouse model of ALS. Neuronal vacuolization in olfaction and vision pathways was assessed in tissue sections from presymptomatic and symptomatic disease stages, and compared to wild type. In both, the olfactory bulb and retina, vacuolization started around postnatal day 60, and vacuole sizes increased until disease end-stage. Notably, vacuolization was largely restricted to the external plexiform layer of the olfactory bulb and to the inner plexiform layer of the retina. In both layers, hSOD1-immunoreactive vacuoles localized to dendrites of excitatory neurons. Downstream olfaction and vision pathway fiber tracts and relay stations did not display obvious vacuolization. Finally, on a morphological level, there was no evidence for an activation of astrocytes and microglia in the 2 affected areas. Thus, we identified a new pathology hallmark in SOD1G93A ALS mice: a glutamatergic sensory neuron dendropathy restricted to olfactory bulb mitral cells and retinal ganglionic cells.


Assuntos
Dendritos/patologia , Inflamação , Neurônios/patologia , Bulbo Olfatório/patologia , Retina/patologia , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Dendritos/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/genética , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Superóxido Dismutase-1/metabolismo
2.
Cell Mol Life Sci ; 74(2): 339-358, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27554772

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Neuronal vacuolization and glial activation are pathologic hallmarks in the superoxide dismutase 1 (SOD1) mouse model of ALS. Previously, we found the neuropeptide calcitonin gene-related peptide (CGRP) associated with vacuolization and astrogliosis in the spinal cord of these mice. We now show that CGRP abundance positively correlated with the severity of astrogliosis, but not vacuolization, in several motor and non-motor areas throughout the brain. SOD1 mice harboring a genetic depletion of the ßCGRP isoform showed reduced CGRP immunoreactivity associated with vacuolization, while motor functions, body weight, survival, and astrogliosis were not altered. When CGRP signaling was completely disrupted through genetic depletion of the CGRP receptor component, receptor activity-modifying protein 1 (RAMP1), hind limb muscle denervation, and loss of muscle performance were accelerated, while body weight and survival were not affected. Dampened neuroinflammation, i.e., reduced levels of astrogliosis in the brain stem already in the pre-symptomatic disease stage, and reduced microgliosis and lymphocyte infiltrations during the late disease phase were additional neuropathology features in these mice. On the molecular level, mRNA expression levels of brain-derived neurotrophic factor (BDNF) and those of the anti-inflammatory cytokine interleukin 6 (IL-6) were elevated, while those of several pro-inflammatory cytokines found reduced in the brain stem of RAMP1-deficient SOD1 mice at disease end stage. Our results thus identify an important, possibly dual role of CGRP in ALS pathogenesis.


Assuntos
Encéfalo/patologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Denervação Muscular , Transdução de Sinais , Superóxido Dismutase-1/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Morte Celular , Quimiocinas/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Hibridização Genética , Linfócitos/patologia , Camundongos Mutantes , Camundongos Transgênicos , Modelos Biológicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Fatores de Crescimento Neural/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/deficiência , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Superóxido Dismutase-1/metabolismo , Vacúolos/metabolismo
3.
PLoS One ; 11(12): e0166901, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936003

RESUMO

Development and maintenance of secondary lymphoid organs such as lymph nodes and spleen essentially depend on lymphotoxin ß-receptor (LTßR) signaling. It is unclear, however, by which molecular mechanism their size is limited. Here, we investigate whether the LTßR pathway is also growth suppressing. By using splenic tissue transplantation it is possible to analyze a potential contribution of LTßR signaling inside and outside of the implanted tissue. We show that LTßR signaling within the endogenous spleen and within non-splenic tissues both significantly suppressed the regeneration of implanted splenic tissue. The suppressive activity positively correlated with the total number of LTßR expressing cells in the animal (regenerate weights of 115 ± 8 mg in LTßR deficient recipients and of 12 ± 9 mg in wild-type recipients), affected also developed splenic tissue, and was induced but not executed via LTßR signaling. Two-dimensional differential gel electrophoresis and subsequent mass spectrometry of stromal splenic tissue was applied to screen for potential factors mediating the LTßR dependent suppressive activity. Thus, LTßR dependent growth suppression is involved in regulating the size of secondary lymphoid organs, and might be therapeutically used to eradicate tertiary lymphoid tissues during autoimmune diseases.


Assuntos
Receptor beta de Linfotoxina/metabolismo , Transdução de Sinais , Baço/metabolismo , Transplante de Tecidos/métodos , Animais , Western Blotting , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Quimiocina CCL19/genética , Quimiocina CCL19/metabolismo , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Eletroforese em Gel Bidimensional , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Receptor beta de Linfotoxina/genética , Espectrometria de Massas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Regeneração , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/crescimento & desenvolvimento , Baço/transplante , Esplenectomia , Células Estromais/metabolismo
4.
Front Physiol ; 6: 87, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25852573

RESUMO

The mouse gastro-intestinal and biliary tract mucosal epithelia harbor choline acetyltransferase (ChAT)-positive brush cells with taste cell-like traits. With the aid of two transgenic mouse lines that express green fluorescent protein (EGFP) under the control of the ChAT promoter (EGFP (ChAT) ) and by using in situ hybridization and immunohistochemistry we found that EGFP (ChAT) cells were clustered in the epithelium lining the gastric groove. EGFP (ChAT) cells were numerous in the gall bladder and bile duct, and found scattered as solitary cells along the small and large intestine. While all EGFP (ChAT) cells were also ChAT-positive, expression of the high-affinity choline transporter (ChT1) was never detected. Except for the proximal colon, EGFP (ChAT) cells also lacked detectable expression of the vesicular acetylcholine transporter (VAChT). EGFP (ChAT) cells were found to be separate from enteroendocrine cells, however they were all immunoreactive for cytokeratin 18 (CK18), transient receptor potential melastatin-like subtype 5 channel (TRPM5), and for cyclooxygenases 1 (COX1) and 2 (COX2). The ex vivo stimulation of colonic EGFP (ChAT) cells with the bitter substance denatonium resulted in a strong increase in intracellular calcium, while in other epithelial cells such an increase was significantly weaker and also timely delayed. Subsequent stimulation with cycloheximide was ineffective in both cell populations. Given their chemical coding and chemosensory properties, EGFP (ChAT) brush cells thus may have integrative functions and participate in induction of protective reflexes and inflammatory events by utilizing ACh and prostaglandins for paracrine signaling.

5.
Neurobiol Dis ; 54: 32-42, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23466699

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Degeneração Neural/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Transdução de Sinais/fisiologia , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imuno-Histoquímica , Hibridização In Situ , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Degeneração Neural/patologia , Superóxido Dismutase/genética , Superóxido Dismutase-1
6.
Neurobiol Dis ; 45(1): 547-54, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21964254

RESUMO

In amyotrophic lateral sclerosis (ALS) some motor neurons degenerate while others survive. The molecular mechanisms underlying this selective vulnerability and resistance, respectively, are poorly understood. Since the neuropeptide, calcitonin gene-related peptide (CGRP), is expressed by many but not all motor neurons, we asked if motor neuron CGRP levels predict their vulnerability in the SOD1-G93A mouse model of ALS. In wild type mice three types of somatic motor neurons were distinguished based on their CGRP expression pattern, i.e. highCGRP, lowCGRP, and nonCGRP. Since motor nuclei III, IV and VI contained mostly nonCGRP motor neurons, they defined the oculomotor group. In comparison, the facial group (nuclei V, VII and XII) contained equal numbers of all three types, while the spinomedullary group (ambiguus nucleus and lumbar spinal cord) contained mainly highCGRP motor neurons. Analysis on the transcript level, and of mice lacking the αCGRP isoform, revealed that these group differences in CGRP expression were predominantly based on αCGRP. At disease end-stage in SOD1-G93A mice, group-specific extent of motor neuron loss correlated with CGRP expression as neurons with highCGRP were reduced by 80%, those with lowCGRP by 50%, and nonCGRP motor neurons were not significantly affected in all three groups. Finally, highCGRP motor neuron degeneration preceded lowCGRP motor neuron degeneration during disease progression. Our analysis revealed that the relative abundance of CGRP mRNA and immunoreactivity in motor neurons predicts their vulnerability. CGRP may be an autocrine or paracrine factor promoting motor neuron degeneration in this ALS model.


Assuntos
Esclerose Lateral Amiotrófica/genética , Peptídeo Relacionado com Gene de Calcitonina/genética , Neurônios Motores/metabolismo , Degeneração Neural/genética , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Expressão Gênica , Masculino , Camundongos , Neurônios Motores/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Superóxido Dismutase/metabolismo
7.
J Neuropathol Exp Neurol ; 69(10): 1057-70, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20838240

RESUMO

The balance between excitatory and inhibitory synaptic inputs is critical for the physiological control of motoneurons. The maintenance of a low-intracellular chloride concentration by the potassium chloride cotransporter 2 (KCC2) is essential for the efficacy of fast synaptic inhibition of mature motoneurons in response to the activation of ionotropic γ-aminobutyric acid A and glycine receptors. Altered synaptic balance and excitotoxicity have been proposed as candidate pathophysiological processes in amyotrophic lateral sclerosis (ALS). Therefore, we investigated the expression patterns of KCC2 and its functional opponent, the chloride influx-mediating sodium-potassium chloride cotransporter 1 (NKCC1), in the superoxide dismutase 1 (SOD1-G93A) mouse model of ALS. We detected reduced KCC2 messenger RNA levels and less membrane-bound KCC2 immunoreactivity in ALS-vulnerable motoneurons in lumbar spinal cord and hypoglossal nuclei of SOD1-G93A mice but not in degeneration-resistant oculomotor nuclei. Downregulation of KCC2 started during late presymptomatic stages and accelerated in parallel to hind limb and tongue motor function deficits. In contrast, NKCC1 messenger RNA levels were unaltered in postnatal lumbar spinal cord motoneurons. Our data indicate that reductions in KCC2 gene expression may contribute to selective motor deficits and disease progression in vulnerable motoneurons in a mouse model of ALS.


Assuntos
Esclerose Lateral Amiotrófica , Regulação para Baixo/genética , Neurônios Motores/metabolismo , Superóxido Dismutase/genética , Simportadores/metabolismo , Fatores Etários , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Análise de Variância , Animais , Animais Recém-Nascidos , Tronco Encefálico/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Medula Espinal/patologia , Simportadores/genética , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Cotransportadores de K e Cl-
8.
Neurobiol Dis ; 35(2): 286-95, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19465128

RESUMO

In our study we investigated the pathology-related expression patterns of the two calcitonin gene-related peptide (CGRP) isoforms in spinal cord motor neurons of SOD1(G93A) mice, an animal model of the human motor neuron disease, amyotrophic lateral sclerosis (ALS). We found that alphaCGRP and betaCGRP gene expression and alphaCGRP immunoreactivity remained unaltered throughout disease, and alphaCGRP gene deficiency had no effect on disease progression. In contrast, betaCGRP immunoreactivity appeared at atypical sites in degenerating motor neuron cell bodies, axons, and dendrites already in the early pre-symptomatic disease phase around postnatal day 40. A close association of betaCGRP-containing dysmorphic dendritic structures with processes of activated astrocytes, in combination with a selective expression of the CGRP receptor by astrocytes, suggests that betaCGRP may function as a motor neuron-derived signaling molecule for astrocyte activation in ALS.


Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Astrócitos/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Gliose/patologia , Neurônios Motores/metabolismo , Envelhecimento , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Astrócitos/patologia , Axônios/patologia , Axônios/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/genética , Dendritos/patologia , Dendritos/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase/genética , Superóxido Dismutase-1
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