RESUMO
Familial Alzheimer disease mutations of presenilin 1 (PS-1) enhance the generation of A beta1-42, indicating that PS-1 is involved in amyloidogenesis. However, PS-1 transgenic mice have failed to show amyloid plaques in their brains. Because PS-1 mutations facilitate apoptotic neuronal death in vitro, we did careful quantitative studies in PS-1 transgenic mice and found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation. However, there were significantly more neurons containing intracellularly deposited A beta42 in aged mutant transgenic mice. Our data indicate that the pathogenic role of the PS-1 mutation is upstream of the amyloid cascade.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Proteínas de Membrana/genética , Neurônios/patologia , Placa Amiloide , Fatores Etários , Peptídeos beta-Amiloides/isolamento & purificação , Animais , Apoptose , Contagem de Células , Humanos , Camundongos , Camundongos Transgênicos , Mutação de Sentido Incorreto , Fragmentos de Peptídeos/isolamento & purificação , Presenilina-1RESUMO
In this report, we establish a regulatory role of natural killer (NK) cells in experimental autoimmune encephalomyelitis (EAE), a prototype T helper cell type 1 (Th1)-mediated disease. Active sensitization of C57BL/6 (B6) mice with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide induces a mild form of monophasic EAE. When mice were deprived of NK cells by antibody treatment before immunization, they developed a more serious form of EAE associated with relapse. Aggravation of EAE by NK cell deletion was also seen in beta 2-microglobulin-/- (beta 2m-/-) mice, indicating that NK cells can play a regulatory role in a manner independent of CD8+ T cells or NK1.1+ T cells (NK-T cells). The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55. EAE passively induced by the MOG35-55-specific T cell line was also enhanced by NK cell deletion in B6, beta 2m-/-, and recombination activation gene 2 (RAG-2)-/- mice, indicating that the regulation by NK cells can be independent of T, B, or NK-T cells. We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation. Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Células Matadoras Naturais/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/biossíntese , Antígenos/imunologia , Antígenos Ly , Antígenos de Superfície , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/genética , Feminino , Interferon gama/deficiência , Interferon gama/genética , Lectinas Tipo C , Ativação Linfocitária/imunologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Proteínas/imunologia , Células Th1/metabolismo , Microglobulina beta-2/deficiência , Microglobulina beta-2/genéticaRESUMO
The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases and cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain binding protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (activating transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.
Assuntos
Apoptose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Neurônios/efeitos dos fármacos , Tiocianatos/farmacologia , Fator 6 Ativador da Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Tiocianatos/químicaRESUMO
Aging is thought to be a risk factor to develop vulnerability of the neuroendocrine system, including the hypothalamic-pituitary-adrenal (HPA) axis, and dysregulation of this axis characterized by dexamethasone (DEX)-mediated negative feedback resistance is sometimes observed in elderly humans and animals. However, the influence of aging on the feedback system including an involvement of the brain is not fully understood. In the present study, we examined the suppressive effects of DEX by the systemic injection or the intracranial infusion into the prefrontal cortex (PFC), hippocampus, and hypothalamus on circulating corticosterone levels, and compared between young (3-month-old) and aged (24-month-old) rats. Moreover, we examined expression levels of glucocorticoid receptors (GRs) and their translocation from the cytoplasm to the nucleus using immunohistochemical and Western immunoblot techniques in the pituitary in addition to three brain regions. When DEX was injected systemically, the suppressive response was significantly enhanced in aged rats, compared with young rats. When DEX was infused into three brain regions, the suppressive response to DEX was abolished in aged rats. The immunohistochemical analysis revealed that the number of GR positive cells in the PFC, hippocampus, and hypothalamus was decreased, but that in the pituitary was increased, in aged rats, compared with young rats. The Western immunoblot analysis confirmed these results. Thus, basal expression levels of GRs in three brain regions were decreased, but those in the pituitary were increased, in aged rats. After the injection or infusion of DEX, the translocation of GRs in three brain regions was reduced, but that in the pituitary was enhanced, in aged rats. These results suggest that aging in rats enhances the feedback ability at the systemic level, which mainly involves the pituitary, but it attenuates the ability in the brain. These mechanisms may underlie the vulnerable neuroendocrine systems associated with aging.
Assuntos
Envelhecimento/fisiologia , Encéfalo/metabolismo , Retroalimentação Fisiológica/fisiologia , Regulação da Expressão Gênica/fisiologia , Glucocorticoides/metabolismo , Fatores Etários , Análise de Variância , Animais , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Contagem de Células , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Corticosterona/sangue , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Radioimunoensaio/métodos , Ratos , Ratos Endogâmicos F344 , Receptores de Glucocorticoides/metabolismoRESUMO
The 39- to 43-amino acid amyloid beta protein (beta AP), which is deposited as amyloid in Alzheimer's disease, is encoded as an internal peptide that begins 99 residues from the carboxyl terminus of a 695- to 770-amino acid glycoprotein referred to as the amyloid beta protein precursor (beta APP). To clarify the processing that produces amyloid, carboxyl-terminal derivatives of the beta APP were analyzed. This analysis showed that the beta APP is normally processed into a complex set of 8- to 12-kilodalton carboxyl-terminal derivatives. The two largest derivatives in human brain have the entire beta AP at or near their amino terminus and are likely to be intermediates in the pathway leading to amyloid deposition.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Amiloide/biossíntese , Fragmentos de Peptídeos/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Linhagem Celular , Membrana Celular/química , Córtex Cerebral/química , Glicosilação , Humanos , Immunoblotting , Técnicas de Imunoadsorção , Peso Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , TransfecçãoRESUMO
We have found that interleukin 3 (IL-3), a growth factor for hematopoietic cells, is a novel trophic factor for mouse and rat central cholinergic neurons. It enhanced neurite outgrowth and elevated choline acetyltransferase activity. The effect seems to be specific for cholinergic neurons, since somatostatin release and glutamic acid decarboxylase and 2',3'-cyclic nucleotide 3'-phosphodiesterase activities were not significantly influenced by IL-3. In vivo, IL-3 was infused into the lateral ventricles of rats after unilateral axotomy of the septohippocampal pathways. Two weeks later, the IL-3-treated animals showed significant numbers of acetylcholinesterase-positive neurons remaining in the septal region.
Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/citologia , Colina O-Acetiltransferase/metabolismo , Interleucina-3/farmacologia , Neurônios/citologia , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Axônios/ultraestrutura , Fatores Biológicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Linhagem Celular , Células Cultivadas , Citocinas , Replicação do DNA/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fatores de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Endogâmicos , Timidina/metabolismoRESUMO
In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1* 1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4+ and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2/2 mice expressing HLA-DR2 (DRG1* 1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to the cerebrum and cerebellum, in association with scattered demyelinating lesions in the deep cerebral cortex. These results support a pathogenic role for PLP95-116-specific T cells in HLA-DR2+ MS patients, and shed light on the possible correlation between autoimmune target epitope and disease phenotype in human CNS autoimmune diseases.
Assuntos
Epitopos de Linfócito T/imunologia , Antígenos HLA-DR/imunologia , Antígeno HLA-DR2/imunologia , Esclerose Múltipla/imunologia , Proteína Proteolipídica de Mielina/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Expressão Gênica , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/genética , Antígeno HLA-DR2/biossíntese , Cadeias HLA-DRB1 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas Nucleares , Fragmentos de Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
We report a novel missense mutation of the Notch3 gene in a Japanese family with CADASIL. The Cys49Gly mutation in this family is located in exon 2 of the Notch3 gene. Most of the documented Notch3 gene mutations occur in exons 3 or 4. On the other hand, there are few reports around the world of mutations in exon 2 of the Notch3 gene, and this is the first report of a mutation in exon 2 of the gene in a Japanese family. In general, CADASIL mutations involve a cysteine residue. Such mutations may influence the tertiary structure of the Notch3 protein, resulting in protein dysfunction. Thus, the CADASIL in the present case may be a consequence of the mutation in exon 2 causing a structural change in the Notch3 protein.
Assuntos
CADASIL/genética , Mutação de Sentido Incorreto , Receptores Notch/genética , Adulto , Povo Asiático , Encéfalo/patologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Doença de Meniere/diagnóstico , Doença de Meniere/genética , Doença de Meniere/patologia , Doença de Meniere/fisiopatologia , Microscopia Eletrônica de Transmissão , Linhagem , Receptor Notch3 , Pele/patologia , Zumbido/fisiopatologia , Vertigem/fisiopatologiaRESUMO
We report here the cDNA sequence of rat homologue of presenilin-2 (PS-2). The rat PS-2 cDNA encoded 448 amino acids, and the deduced amino acid sequence was highly homologous to those of the human (94.9%), mouse (96.4%) and Xenopus (70.8%). A minor splicing variant lacking a single glutamate was detected, while the product corresponding to the exon 9 deleted splicing variant observed in human was not detected.
Assuntos
Clonagem Molecular , DNA Complementar/isolamento & purificação , Proteínas de Membrana/genética , Processamento Alternativo , Doença de Alzheimer/genética , Sequência de Aminoácidos , Animais , Encéfalo , Humanos , Leucócitos , Proteínas de Membrana/isolamento & purificação , Camundongos , Dados de Sequência Molecular , Presenilina-2 , Ratos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , XenopusRESUMO
We studied the polymorphism of alpha1-antichymotrypsin (ACT), very low density lipoprotein receptor (VLDLR) and apolipoprotein E (ApoE) genes in 200 control subjects and 65 patients with Alzheimer's disease (AD) in Japanese. The subjects consisted of 30 patients with early onset familial Alzheimer's disease (FAD), a patient with late onset FAD, 29 patients with an early onset isolated form of AD, and 5 patients with late onset AD. ApoE genotypes were significantly different between controls and FAD (p < 0.0005) or AD (p < 0.05), and patients carrying at least one ApoE epsilon4 allele were found in 44% of FAD and 34.3% of AD; both were significantly different (p < 0.001) from the controls (12.5%). ACT genotypes and allele frequencies were not different among these groups except for genotypes between ApoE epsilon4 FAD and ApoE epsilon4 controls (p = 0.019). There was a slight but significant increase of the 5 repeat allele of VLDLR in AD (p = 0.014), but the difference was rather diminished in the presence of an ApoE epsilon4 allele. None of combinations of ACT and VLDLR genotypes in the presence or absence of an ApoE epsilon4 allele gave significant difference. Thus, we conclude that among the reported genetic risk factors, ApoE epsilon4 is the only definite risk factor for both FAD and AD, and the VLDLR polymorphism might be associated with AD cases in Japanese.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Receptores de LDL/genética , alfa 1-Antiquimotripsina/genética , Alelos , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Biomarcadores , Feminino , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação/genética , Receptores de LDL/metabolismo , Fatores de Risco , alfa 1-Antiquimotripsina/metabolismoRESUMO
The main characteristic changes observed in Alzheimer's disease (AD) are the presence of neurofibrillary tangles and the deposition of amyloid A4 peptides. The most abundant amyloid A4 peptide species in AD (which we tentatively named A4') is composed of 39 amino acids, which is devoid of the 3 N-terminal amino acids, Asp-Ala-Glu, of the originally reported A4 peptide. We synthesized a model peptide substrate, Suc-Ala-Glu-methylcoumarinamide (MCA), to identify the proteinase that splits the A4' peptide. DEAE-cellulose column chromatography of rat liver and porcine brain extracts showed that only one peak material digested the synthetic substrate at pH 8. The results for the final preparation indicate that the Suc-Ala-Glu-MCA-degrading enzyme is a high-molecular-mass proteinase, with a molecular mass of above 500,000, and is composed of several low-molecular-mass subunits. These results suggest that a non-lysosomal multicatalytic proteinase (we named this enzyme ingensin (ingens = large in Latin). Ishiura, S. et al. (1985) FEBS Lett. 189, 119-123) catalyzes the above reaction. Antiserum against the purified multicatalytic proteinase, ingensin, crossreacted with the purified Suc-Ala-Glu-MCA-degrading proteinase. It is likely that ingensin shows a similar action toward amyloid precursor protein (APP) in vivo.
Assuntos
Amiloide/metabolismo , Cisteína Endopeptidases/metabolismo , Complexos Multienzimáticos/metabolismo , Precursores de Proteínas/metabolismo , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide , Animais , Western Blotting , Cromatografia DEAE-Celulose , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Dados de Sequência Molecular , Peso Molecular , Complexo de Endopeptidases do Proteassoma , Ratos , Distribuição TecidualRESUMO
Missense mutations and intronic mutations in the tau gene cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known missense mutations reduce the ability of tau to promote microtubule assembly. Intronic mutations lead to increased mRNA splicing of the alternatively spliced exon 10, resulting in an overproduction of tau isoforms with four microtubule-binding repeats. We show here that the recently identified FTDP-17 missense mutations N279K and S305N do not reduce the ability of tau to promote microtubule assembly. Instead they lead to increased splicing of exon 10, like the intronic mutations. The N279K and S305N mutations define a class of missense mutations in tau whose primary effects are at the RNA level.
Assuntos
Processamento Alternativo , Éxons , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Proteínas tau/genética , Sequência de Aminoácidos , Sequência de Bases , DNA , Humanos , Íntrons/genética , Mutagênese Sítio-Dirigida , Proteínas Recombinantes/genéticaRESUMO
Three cases of reflex sympathetic dystrophy (causalgia) were associated with cervical spondylosis. Two of them were related to sudden cervical trauma. Patients showed burning pain, hyperalgesia in a segmental distribution, and edema of the arms, hands, and fingers bilaterally. Oral administration of guanethidine sulfate was effective in all cases. Our results support the hypothesis that hypersensitivity to norepinephrine plays a role in reflex sympathetic dystrophy.
Assuntos
Causalgia/tratamento farmacológico , Guanetidina/uso terapêutico , Neuralgia/tratamento farmacológico , Idoso , Causalgia/complicações , Causalgia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Coluna Vertebral/complicaçõesRESUMO
BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.
Assuntos
Cromossomos Humanos Par 17 , Demência/genética , Saúde da Família , Mutação Puntual , Proteínas tau/genética , Primers do DNA , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
An 8-year-old girl had progressive muscle weakness and a unique posture of the lower limbs, areflexia, distal sensory impairment, and remarkably kinky hair. Histologic examination of the sural nerve showed giant axons filled with neurofilamentous masses. The clinical and histologic findings resembled those of recent cases reported as "giant axonal neuropathy." Our patient's precocious puberty, Babinski's sign, and electroencephalographic abnormalities suggested central nervous system involvement. Two cases previously reported and the present one appear to represent a new clinical entity that affects the central and the peripheral nervous system.
Assuntos
Axônios/patologia , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Periférico/patologia , Axônios/ultraestrutura , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/fisiopatologia , Criança , Eletroencefalografia , Feminino , Marcha , Cabelo , Humanos , Condução Nervosa , Linhagem , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Puberdade Precoce/etiologia , Reflexo de Babinski , Nervo Sural/patologiaRESUMO
OBJECTIVE: To characterize the clinical diagnostic features, neuropathologic phenotype of tau deposition, and subunit structure of tau filaments in patients who had an asparagine-to-lysine substitution at codon 279 (the N279K missense mutation) of the gene for microtubule-associated tau protein. BACKGROUND: The N279K mutation is a causative genetic defect for pallidopontonigral degeneration in an American kindred that presents with frontotemporal dementia (FTD) and parkinsonism. METHODS: The authors analyzed retrospectively the clinical symptoms of two Japanese brothers who carry this mutation. Postmortem neuropathologic and electron microscopic studies, and Western blot analysis of insoluble tau were performed to correlate tau-mediated lesions with neurologic deficits. RESULTS: Both patients exhibited impairment in recent memory, parkinsonism, and corticospinal disturbances in addition to FTD. Parkinsonism in one patient was responsive temporarily to l-dopa. There was intense tau deposition in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration. Two distinct tau isoforms with four microtubule-binding repeats, in hyperphosphorylated forms, were the primary constituents of insoluble tau, which aggregated to the filamentous component, termed "paired tubules," in neurons, oligodendrocytes, and astrocytes. The elemental filaments were hollow tubules measuring 11 to 12 nm in diameter, two of which adhered to each other along their longitudinal axes to form "paired tubules." CONCLUSIONS: Early memory loss and pyramidal signs, which are atypical of FTD, can be presenting symptoms in this disorder. The authors demonstrated that the subunit structure of tau filaments is a pair of hollow tubules despite the prevailing twisted ribbon model.
Assuntos
Substituição de Aminoácidos/genética , Códon/genética , Demência/genética , Mutação de Sentido Incorreto/genética , Transtornos Parkinsonianos/genética , Proteínas tau/genética , Asparagina/genética , Demência/diagnóstico , Demência/patologia , Diagnóstico Diferencial , Lobo Frontal/patologia , Humanos , Lisina/genética , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Neurônios Motores/patologia , Exame Neurológico , Testes Neuropsicológicos , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/patologia , Linhagem , Tratos Piramidais/patologia , Estudos Retrospectivos , Lobo Temporal/patologiaRESUMO
Abeta plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), but it is still obscure how it causes AD. We have established transgenic mice carrying wild-type or familial Alzheimer's disease (FAD) mutant-type presenilin 1 (PS1). In these mice, the number of cortical and hippocampal neurons decreased along with age in mutant mice. In addition, the old mutant mice showed a significant increase of dark neurons by silver staining and the number of neurons with intracellular Abeta42 by immunohistochemistry. Our extended study also showed a significant increase of intracellular Abeta42-positive neurons in isolated cases of AD as well as in PS1 mutant FAD cases. These neurons frequently showed apoptotic staining. However, coincidence of apoptotic markers and intraneuronal neurofibrillary tangles (NFT) was insignificant. Notably intraneuronal Abeta42-labeling was frequently seen in a case of AD showing cotton-wool type senile plaques with a few NFT positive neurons and dystrophic neurites. These results indicate that intraneuronal deposition of Abeta42 is important in the pathogenesis of AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Animais , Apoptose , Encéfalo/metabolismo , Encéfalo/patologia , Citoplasma/metabolismo , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/imunologia , Presenilina-1RESUMO
The suppressive effect of anti-L3T4 monoclonal antibody (mAb) on murine experimental allergic encephalomyelitis (EAE) induced by sensitization with proteolipid apoprotein (PLP) was examined in vivo and in vitro. This mAb inhibited the antigen-specific proliferation of the encephalitogenic T cell lines but did not block the mitogen-mediated response. Serial injections of the mAb during the pre-effector phase of EAE markedly suppressed the development and relapse of the disease but this treatment initiated after appearance of clinical signs was not effective. In treated animals, L3T4+ T cells in the spleen were profoundly decreased and the antigen-specific proliferative response of spleen cells was completely suppressed. Moreover, adoptive transfer of spleen cells from the treated mice induced resistance against EAE induction in the recipients. However, no obvious evidence for antigen-specific suppressor cells was found in vitro in the L3T4- populations of spleen cells from treated mice.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos de Diferenciação de Linfócitos T/imunologia , Apoproteínas , Encefalomielite Autoimune Experimental/prevenção & controle , Proteínas da Mielina , Proteína Proteolipídica de Mielina , Doença Aguda , Animais , Anticorpos Monoclonais/farmacologia , Antígenos de Superfície/análise , Esquema de Medicação , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Epitopos/imunologia , Feminino , Imunização Passiva , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Recidiva , Baço/citologiaRESUMO
Lewis rats that have recovered from EAE induced by the passive transfer of in vitro activated lymphocytes sensitized to myelin basic protein showed suppression upon subsequent active reinduction of EAE. This suppression was manifested during the early convalescent stage (up to 30 days after the primary cell transfer) and seemed to be acquired partly idiotype-specifically and partly idiotype-nonspecifically. The convalescent rats were fully susceptible to the transfer of sufficient numbers of effector cells, and they could induce pre-effector cells in response to the encephalitogen in vivo as effectively as in naive rats. This suppression was not transferred to naive rats by lymphoid cells from the convalescent rats. The mechanism of this suppression was thought to be a defect in expansion and/or differentiation of pre-effector cells to effector cells in the convalescent rats.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Tolerância Imunológica , Imunização Passiva , Animais , Células Cultivadas , Feminino , Proteína Básica da Mielina/imunologia , Ratos , Ratos Endogâmicos Lew , Linfócitos T/imunologia , Fatores de TempoRESUMO
The effect of chemical sympathectomy induced with 6-hydroxydopamine (OHDA) on experimental autoimmune encephalomyelitis (EAE) was studied in wild type and IL-4-/- C57BL/6 (B6) mice. When actively sensitized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, control B6 mice developed a mild form of EAE with full recovery. The sympathectomized mice developed paralysis with higher maximum disease score and did not recover completely, indicating that the sympathetic nervous system (SNS) down-modulates the process of EAE. Unexpectedly, however, sympathectomy resulted in suppression of EAE in IL-4-/- mice, implying that control of actively induced EAE by the SNS depends on the genetic background of mice. We also induced EAE by passive transfer of MOG35-55-reactive lymph node cells, and this disease was augmented by sympathectomy in both wild type and knockout animals. Further experiments showed that changes in T cell populations and the activity of antigen presenting cells might be responsible for the altered immune response and clinical course after sympathetic ablation. Our studies indicate that the absence of a single cytokine can severely alter nervous-immune system interactions.