RESUMO
Pallido-nigro-luysial atrophy (PNLA) is a rare disorder that in many cases has histopathological features similar to progressive supranuclear palsy (PSP). In a pathological series of over 400 cases of PSP, eight cases were noted to have features similar to those described in PNLA, including severe atrophy and neuronal loss in the globus pallidus, substantia nigra and subthalamic nucleus, in addition to many axonal spheroids in the globus pallidus and substantia nigra. These eight cases of PSP-PNLA were compared to 11 typical PSP cases with quantitative neuropathologic indices and assessment of demographics, clinical features and the timing of clinical features. PSP-PNLA cases were younger, had longer disease duration and more often were not initially diagnosed with PSP; in the end, they did not differ from PSP with respect to any major clinical feature. The clinical course of PSP-PNLA, however, was different, with earlier gait abnormalities and difficulty with handwriting, but later falls, rigidity and dysphagia than PSP. Pathologically, the same types of lesions were detected in both PSP and PSP-PNLA, but there were differences in the distribution and density of tau-pathology, with less tau-pathology in motor cortex, striatum, pontine nuclei and cerebellum in PSP-PNLA. These clinical and pathological findings suggest that PSP-PNLA should be considered a variant of PSP.
Assuntos
Axônios/patologia , Encéfalo/patologia , Paralisia Supranuclear Progressiva/diagnóstico , Idoso , Atrofia/complicações , Atrofia/diagnóstico , Atrofia/patologia , Transtornos Cognitivos/etiologia , Progressão da Doença , Feminino , Transtornos Neurológicos da Marcha/etiologia , Globo Pálido/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Substância Negra/patologia , Núcleo Subtalâmico/patologia , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/metabolismo , Paralisia Supranuclear Progressiva/patologia , Transtornos da Visão/etiologia , Proteínas tau/análiseRESUMO
In this study, we used immunohistochemistry to screen for alpha-synuclein pathology in the brains of 241 individuals without clinical evidence of neurologic disease, and discovered 36 cases (15%) with incidental Lewy bodies (LBs) and one case, a 96-year-old woman (0.4%), with inclusions similar to those seen in multiple system atrophy (MSA), a non-familial neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction and alpha-synuclein immunoreactive glial cytoplasmic inclusions (GCI). In a routine hospital autopsy series of 125 brains, we detected GCI in a neurologically normal 82-year-old man (0.8%). Both cases showed widespread GCI in the central nervous system, as well as a few neuronal cytoplasmic inclusions, but no neuronal loss or gliosis in vulnerable brain regions, including the substantia nigra, putamen, inferior olive and pontine base. Applying a recently proposed grading scale for MSA, the two cases showed pathology far below that detected in patients with clinically overt MSA, suggesting the possibility that these two individuals had preclinical MSA. The prevalence of clinically overt MSA is estimated to be about 4 per 100,000 persons (0.004%), which is far less than the frequency of GCI in this series (0.4-0.8%). Further studies are needed to determine if GCI in neurologically normal elderly represents prodromal MSA or a rare non-progressive age-related alpha-synucleinopathy.
Assuntos
Corpos de Inclusão/metabolismo , Corpos de Lewy/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Neuroglia/metabolismo , alfa-Sinucleína/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Técnicas Imunoenzimáticas , Corpos de Inclusão/patologia , Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/patologia , Neuroglia/patologiaRESUMO
Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = -0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = -0.61, P < 0.001), and disease duration (r = -0.63, P < 0.001). Immunohistochemistry for alpha-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of alpha-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity.
Assuntos
Coração/inervação , Degeneração Neural/patologia , Doença de Parkinson/patologia , Sistema Nervoso Simpático/patologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Progressão da Doença , Feminino , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/patologia , Corpos de Lewy/patologia , Masculino , Fibras Nervosas/patologia , Neuritos/patologia , Doença de Parkinson/diagnóstico , Pericárdio/inervação , Pericárdio/patologia , Medula Espinal/patologia , Tirosina 3-Mono-Oxigenase/análise , alfa-Sinucleína/análiseRESUMO
We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ligante de CD40/metabolismo , Gliose/genética , Neurônios/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Feminino , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Neurônios/patologia , Placa Amiloide/patologia , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies (LBs) are detected in approximately 10% of PSP cases, but there is little information on the relationship of LBs to tau pathology. We determined the frequency of LBs in a large series of autopsy-confirmed cases of PSP and studied the density and distribution of LBs, including Parkinson disease stage, in cases with LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including assessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for alpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple system atrophy in addition to PSP and was excluded from further study along with 2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were compared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, Braak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile plaques were not different among PSP, LBD, and PSP/LBD, but disease duration was longer in LBD. The Parkinson disease stage was similar, but the density of LBs in most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In contrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP and LBD. Double immunostaining demonstrated alpha-synuclein and tau in different neurons with few exceptions. The findings suggest that LBs in PSP are similar in distribution to those in LBD and independent of tau pathology. The greater density of LBs in LBD compared with PSP/LBD may be the result of longer disease duration in LBD, whereas greater neuronal loss in the substantia nigra in PSP/LBD may be the result of vulnerability of this brain region to both disease processes.
Assuntos
Tronco Encefálico/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/patologia , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/metabolismo , Feminino , Imunofluorescência , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/metabolismo , Masculino , Microscopia Confocal , Emaranhados Neurofibrilares/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Sinucleínas/metabolismo , Proteínas tau/metabolismoRESUMO
The involvement of beta-secretase and gamma-secretase in producing the beta-amyloid component of senile plaques found in the brain of Alzheimer's patients has fueled a major research effort to design selective inhibitors of these proteases. Interestingly, gamma-secretase cleaves several proteins including Notch, E-cadherin, CD44 and ErbB-4 (erythroblastic leukemia viral oncogene homolog 4), which are important modulators of angiogenesis. The beta-amyloid precursor protein, which is cleaved by beta-secretase and gamma-secretase to produce beta-amyloid, is highly expressed in the endothelium of neoforming vessels suggesting that it might play a role during angiogenesis. These data prompted us to explore the effects of beta and gamma-secretase inhibitors of different structures on angiogenesis and tumor growth. Both the gamma and beta-secretase inhibitors tested reduce endothelial cell proliferation without inducing cellular toxicity, suppress the formation of capillary structures in vitro and oppose the sprouting of microvessel outgrowths in the rat aortic ring model of angiogenesis. Moreover, they potently inhibit the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumors xenotransplanted into nude mice. Altogether these data suggest that the gamma and beta-secretases play an essential role during angiogenesis and that inhibitors of the beta and gamma-secretases may constitute new classes of anti-angiogenic and anti-tumoral compounds.
Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Neoplasias Experimentais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Secretases da Proteína Precursora do Amiloide , Análise de Variância , Animais , Encéfalo/citologia , Capilares/efeitos dos fármacos , Capilares/crescimento & desenvolvimento , Carbamatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Endopeptidases , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Nus , Morfogênese/efeitos dos fármacos , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/patologia , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It has been demonstrated that immunization of transgenic mouse models of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) results in prevention of Abeta plaque formation and amelioration of established plaques in the brain. As the response of the T lymphocyte helper (Th) arm of the immune response had not yet been investigated after Abeta immunization, we i.p. immunized C57BL/6 mice with Abeta(1-42), Abeta(1-40), or phosphate-buffered saline (PBS), and examined markers of Th1 and Th2 immune responses in spleen and in splenocytes from these mice. Spleens from Abeta(1-42)-immunized mice demonstrated decreased interleukin-12 receptor beta chain expression compared to mice immunized with Abeta(1-40) or PBS. Consistently, following stimulation with concanavalin A or anti-CD3 antibody, primary splenocytes from Abeta(1-42)-immunized mice demonstrated elevated secretion of interleukin-4 and interleukin-10, and decreased levels of interferon-gamma. To validate this Th1-->Th2 shift in a transgenic mouse model of AD, we immunized Tg APP(sw) mice (line 2576) with Abeta(1-42) and found decreased Th1 (interleukin-2 and interferon-gamma) and elevated Th2 (interleukin-4 and interleukin-10) cytokines in their stimulated primary splenocytes. Interferon-gamma was markedly reduced and interleukin-10 was increased in blood plasma from these mice, effects that were associated with dramatically mitigated Abeta deposition after Abeta(1-42) immunization. Taken together, these results show enhanced Th2 and down-regulated Th1 immunity following immune challenge with Abeta(1-42).
Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Fragmentos de Peptídeos/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Feminino , Imunização , Imunoglobulina G/classificação , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-4/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Abeta peptides are naturally occurring peptides, which are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). In AD cases, levels of soluble and insoluble Abeta peptides increase in the brain as well as in the cerebrovasculature, a phenomenon that does not occur in extra-cranial vessels. There are frequently anomalies in the cerebrovasculature in AD, and despite increases in several pro-angiogenic factors in AD brain, evidence for increased vascularity is lacking; in fact there is evidence to the contrary. It has also been recently shown that Abeta peptides may have profound anti-angiogenic effects in vitro and in vivo. We therefore investigated whether there is evidence for altered angiogenesis in the vasculature in a transgenic mouse model of Abeta amyloidosis (Tg APPsw line 2576). In vitro, the formation of capillary-like structures on a reconstituted extracellular matrix by endothelial cells isolated from Tg APPsw is impaired. Ex vivo, the sprouting of new capillaries from arterial explants (over expressing Abeta) isolated from 9-month-old Tg APPsw is reduced compared to arterial explants isolated from control littermates. In addition, Tg APPsw mice show a reduction in vascular density in the cortex and hippocampus compared to control littermates. Altogether, our data suggest that the over expression of APPsw in the vasculature may oppose angiogenesis.
Assuntos
Peptídeos beta-Amiloides/biossíntese , Amiloidose/patologia , Encéfalo/patologia , Neovascularização Patológica/patologia , Envelhecimento/patologia , Amiloidose/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Córtex Cerebral/irrigação sanguínea , Colágeno , Combinação de Medicamentos , Células Endoteliais/patologia , Hipocampo/irrigação sanguínea , Técnicas In Vitro , Laminina , Camundongos , Camundongos Transgênicos , Microcirculação/metabolismo , Microcirculação/patologia , Neovascularização Patológica/metabolismo , Proteoglicanas , Veias Cavas/metabolismo , Veias Cavas/patologiaRESUMO
Lewy pathology occurs in 8-17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
Assuntos
Demência/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , Estudos Retrospectivos , alfa-Sinucleína/isolamento & purificaçãoRESUMO
BACKGROUND: Insulin-degrading enzyme (IDE) is a widely studied zinc-metalloprotease implicated in the pathogenesis of type 2 diabetes mellitus, Alzheimer disease (AD) and varicella zoster virus infection. Despite more than six decades of research on IDE, progress has been hampered by the lack of well-characterized reagents targeting this biomedically important protease. To address this important need, we generated and characterized new mouse monoclonal antibodies (mAbs) targeting natively folded human and rodent IDE. RESULTS: Eight monoclonal hybridoma cell lines were derived in house from mice immunized with full-length, natively folded, recombinant human IDE. The mAbs derived from these lines were shown to detect IDE selectively and sensitively by a wide range of methods. Two mAbs in particular-designated 6A1 and 6H9-proved especially selective for IDE in immunocytochemical and immunohistochemical applications. Using a variety of methods, we show that 6A1 selectively detects both human and rodent IDE, while 6H9 selectively detects human, but not rodent, IDE, with both mAbs showing essentially no cross reactivity with other proteins in these applications. Using these novel anti-IDE mAbs, we also developed sensitive and quantitative sandwich ELISAs capable of quantifying IDE levels present in human brain extracts. CONCLUSION: We succeeded in developing novel mAbs that selectively detect rodent and/or human IDE, which we have shown to be suitable for a wide range of applications, including western blotting, immunoprecipitation, immunocytochemistry, immunohistochemistry, and quantitative sandwich ELISAs. These novel anti-IDE mAbs and the assays derived from them constitute important new tools for addressing many unresolved questions about the basic biology of IDE and its role in multiple highly prevalent human diseases.
RESUMO
Non-motor manifestations of Parkinson disease (PD) are common and some may actually antedate motor dysfunction. Extrapyramidal signs in PD are tightly linked to striatonigral dopaminergic denervation associated with neuronal loss and Lewy bodies in the residual neurons of the substantia nigra. Lewy bodies composed of abnormal alpha-synuclein are the histologic hallmark of PD, and their presence beyond midbrain dopaminergic neurons is considered to be the pathologic substrate of many, if not all, of the non-motor manifestations of PD. We review the pathologic correlates of autonomic dysfunction (cardiac and gastrointestinal), hyposmia, depression, rapid eye movement behavior disorder and dementia in PD For each non-motor clinical feature there is strong evidence to suggest a role for alpha-synuclein pathology, lending further support for the notion that PD is a multisystem alpha-synucleinopathy.
Assuntos
Corpos de Lewy/patologia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/patologia , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/metabolismo , Doenças do Sistema Nervoso Autônomo/patologia , Demência/etiologia , Demência/metabolismo , Demência/patologia , Depressão/etiologia , Depressão/metabolismo , Depressão/patologia , Humanos , Transtorno do Comportamento do Sono REM/etiologia , Transtorno do Comportamento do Sono REM/metabolismo , Transtorno do Comportamento do Sono REM/patologiaRESUMO
OBJECTIVE: To explore whether associations of potential risk factors for incidental Lewy body disease (iLBD) are similar to those for Parkinson disease (PD). DESIGN: Brain autopsy study (1988-2004) of subjects without evidence of neurodegenerative disease or tremor who were evaluated by at least 1 physician within 1 year of death. Researchers analyzed incidental Lewy pathology blinded to clinical abstraction. SETTING: Olmsted County, Minnesota. Subjects Residents of Olmsted County and the immediate vicinity aged older than 60 years. MAIN OUTCOME MEASURES: Whether risk factors previously associated with PD in Olmsted County are also associated with iLBD. RESULTS: Of 235 subjects, 34 had iLBD (14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the 2 sets of odds ratio (OR) estimates, with 11 of 16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for physician occupation and caffeine intake, the ORs for iLBD were in the same direction and statistically significant, whereas for education, head injury, and number of children, they were in the same direction but not significant; they were in the opposite direction but not statistically significant for depression and anxiety. Incidental Lewy body disease was not associated with various end-of-life conditions or causes of death, though these patients were slightly older and more likely cachectic. CONCLUSIONS: Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of iLBD could represent preclinical PD, arrested PD, or a partial syndrome due to a lesser burden of causative factors. Incidental Lewy body disease is not explained by nonspecific end-of-life brain insults.
Assuntos
Encéfalo/patologia , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/patologia , Adolescente , Adulto , Idoso , Autopsia , Encéfalo/fisiopatologia , Causalidade , Criança , Pré-Escolar , Exposição Ambiental/estatística & dados numéricos , Feminino , Humanos , Lactente , Doença por Corpos de Lewy/fisiopatologia , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Minnesota/epidemiologia , Razão de Chances , Doença de Parkinson/fisiopatologia , Sistema de Registros , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Lewy bodies, the histologic hallmark of Parkinson's disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.
Assuntos
Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/etiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/patologia , Morte Celular , Distribuição de Qui-Quadrado , Feminino , Humanos , Incidência , Doença por Corpos de Lewy/patologia , Masculino , Miocárdio/metabolismo , Doença de Parkinson/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
BACKGROUND: The significance of Lewy bodies detected at autopsy in the brains of clinically normal individuals is uncertain but may represent preclinical Parkinson disease (PD). OBJECTIVE: To determine whether diminished striatal dopaminergic innervation and nigral cell loss are present in incidental Lewy body disease (iLBD), as one might expect if it is a forerunner of PD. DESIGN: Case-control study. SETTING: Medical records and archival brain tissue were obtained from a tertiary medical center for further study. PARTICIPANTS: Brains from clinically healthy individuals older than 60 years with alpha-synuclein-immunoreactive Lewy bodies (iLBD; n = 12) were compared with those from clinically healthy individuals with no alpha-synuclein pathologic findings (n = 31) and patients with PD (n = 25). MAIN OUTCOME MEASURES: Striatal dopaminergic integrity assessed in sections of putamen by immunofluorescence for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2), neuronal loss score in the substantia nigra, and distribution of Lewy bodies according to PD stage. RESULTS: Among the participants with iLBD, decreased striatal dopaminergic immunoreactivity was documented for both TH (33%) and VMAT2 (42%), compared with the pathologically normal subjects; as expected, the reductions were even greater in PD (73% decrease for TH and 96% decrease for VMAT2). Substantia nigra neuronal loss inversely correlated with both striatal TH (r = -0.84) and VMAT2 (r = -0.77). In addition, PD stage inversely correlated with both striatal VMAT2 (r = -0.85) and TH (r = -0.85). CONCLUSIONS: The results indicate that iLBD has nigrostriatal pathological features that are intermediate between those in pathologically normal persons and those with PD. The findings suggest that iLBD probably represents presymptomatic PD, rather than nonspecific, age-related alpha-synuclein pathological changes.
Assuntos
Achados Incidentais , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. The neuropathology is characterized by neurofibrillary tangles, tufted astrocytes, and coiled bodies, but some brains show other pathologic processes. To investigate the frequency of alpha-synuclein pathology in PSP with immunohistochemistry and to report the clinical and pathological features of a case of PSP with concomitant Multiple system atrophy (MSA) (PSP/MSA), 290 cases of PSP were screened for alpha-synuclein pathology with immunohistochemistry. Double-labeling immunohistochemistry was performed on a case of PSP/MSA. Among the PSP cases screened for alpha-synuclein pathology, a single case of PSP/MSA was detected. The patient was an 86-year-old woman with clinical features consistent with PSP. She had no documented dysautonomia or cerebellar signs, and imaging studies were not diagnostic of MSA. Pathological examination showed tau-immunoreactive neuronal and glial lesions consistent with PSP as well as alpha-synuclein immunoreactive glial cytoplasmic inclusions diagnostic of MSA. Double-immunolabeling studies showed no co-localization of alpha-synuclein and tau in most neuronal and glial lesions. Based upon the findings in this case, the neuropathologic changes of PSP and MSA are distinct and independent processes, but they can occasionally coexist.
Assuntos
Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/patologia , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/patologia , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/metabolismo , Corpos de Inclusão/ultraestrutura , Atrofia de Múltiplos Sistemas/metabolismo , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/metabolismo , Distribuição Tecidual , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMO
We show here that CD40 mRNA and protein are expressed by neuronal cells, and are increased in differentiated versus undifferentiated N2a and PC12 cells as measured by RT-PCR, western blotting and immunofluorescence staining. Additionally, immunohistochemistry reveals that neurons from adult mouse and human brain also express CD40 in situ. CD40 ligation results in a time-dependent increase in p44/42 MAPK activation in neuronal cells. Furthermore, ligation of CD40 opposes JNK phosphorylation and activity induced by NGF-beta removal from differentiated PC12 cells or serum withdrawal from primary cultured neurons. Importantly, CD40 ligation also protects neuronal cells from NGF-beta or serum withdrawal-induced injury and affects neuronal differentiation. Finally, adult mice deficient for the CD40 receptor demonstrate neuronal dysfunction as evidenced by decreased neurofilament isoforms, reduced Bcl-x(L):Bax ratio, neuronal morphological change, increased DNA fragmentation, and gross brain abnormality. These changes occur with age, and are clearly evident at 16 months. Taken together, these data demonstrate a role of CD40 in neuronal development, maintenance and protection in vitro and in vivo.
Assuntos
Antígenos CD40/metabolismo , Neurônios/metabolismo , Animais , Western Blotting , Antígenos CD40/genética , Diferenciação Celular , Linhagem Celular , Meios de Cultura Livres de Soro , Ativação Enzimática , Humanos , Imuno-Histoquímica , Proteínas Quinases JNK Ativadas por Mitógeno , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/imunologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid-beta peptides (Abeta) as senile plaques and by the occurrence of neurofibrillary tangles (NFTs) composed primarily of hyperphosphorylated tau protein. Activation of cyclin-dependent kinase 5 (Cdk5) via its potent activator p25 has recently been shown to promote phosphorylation of tau at AD-specific phosphoepitopes, and increased cleavage of p35 to p25 has been demonstrated in AD patients, suggesting that Cdk5 may represent a pathogenic tau protein kinase. We were interested in the potential effect of soluble forms of Abeta on Cdk5-mediated AD-like tau phosphorylation, insofar as previous studies of human biopsies and aged canine and primate brains have shown that dystrophic neurites appear before the formation of neuritic plaques. We transfected N2a cells with a p35 vector (N2a/p35 cells) and, after differentiation, challenged these cells with Abeta(1-42) peptide in soluble form (sAbeta(1-42)). Results show that sAbeta(1-42) at relatively low levels (1-5 microM) dose-dependently increases tau phosphorylation at AD-specific phosphoepitopes in differentiated N2a/p35 cells compared with controls, an effect that is blocked by antisense oligonucleotides against p35. sAbeta(1-42)-induced tau phosphorylation is concomitant with an increase in both p25 to p35 ratio and Cdk5 activity (but not protein levels). Additionally, blockade of L-type calcium channels or inhibition of calpain completely abolishes this effect. Taken together, these data indicate that sAbeta is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD-like tau phosphorylation in vitro.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/farmacologia , Animais , Western Blotting , Canais de Cálcio Tipo L/metabolismo , Calpaína/metabolismo , Técnicas de Cultura de Células , Quinase 5 Dependente de Ciclina , Relação Dose-Resposta a Droga , Vetores Genéticos , Humanos , Imuno-Histoquímica , Fosforilação/efeitos dos fármacos , Transdução de Sinais , Transfecção , Regulação para Cima/efeitos dos fármacos , Proteínas tau/efeitos dos fármacosRESUMO
Abeta peptides are naturally occurring peptides forming beta-sheet aggregates that constitute an integral component of senile plaques and vascular deposits in Alzheimer's disease. Since several peptides adopting a beta-sheet conformation have been shown to be anti-angiogenic, we investigated the effect of Abeta on angiogenesis. We show that in vitro, Abeta dose-dependently inhibits the formation of capillaries by human brain endothelial cells plated on Matrigel and stimulates capillary degeneration at high doses. Preparations of Abeta peptides containing a higher content of beta-sheet structures are more potently anti-angiogenic in vitro. Ex vivo, Abeta dose-dependently opposes angiogenesis in rat aortae and in human middle cerebral arteries. In vivo, Abeta dose dependently inhibits angiogenesis in the chick chorioallantoic membrane assay and suppresses bFGF-induced blood vessel formation in the corneal micropocket and Matrigel plug assays. Since angiogenesis is required for tumor growth, we explored the effect of Abeta on human glioblastoma (U87MG) and human lung adenocarcinoma (A549) tumors. We show that intra-tumoral injection of Abeta potently inhibits the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumor xenografts in nude mice. Similarly to the intra-tumoral injection regimen, Abeta delivered intraperitoneally also suppressed the growth of human lung adenocarcinoma tumor xenografts. Altogether our data show that Abeta is an angiogenesis inhibitor.