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This study aimed to analyze the use of public open spaces and physical activity levels among children and adolescents in the city of Rivera, Uruguay. A total of 88 target areas located in 29 public open spaces were observed using the System for Observing Play and Recreation in Communities (SOPARC). Systematic observations were made at different times of the day, covering both weekdays and weekends, for a total of 792 records in each public open spaces. Characteristics of the users were recorded according to gender (male and female), age group (infancy to early childhood 0-5 years, middle childhood 6-12 years, adolescence 13-18 years) and physical activity level (sedentary, moderate, or vigorous activity). Logistic regression was employed, considering variables such as day, period, type, and conditions, to assess factors associated with user presence and activity, with separate analyses by gender. Most of the users were adolescents (59.8%) between 13 and 18 years, 67.2% were male and half of the users were sedentary (50.1%). Furthermore, the majority of participants used the target areas on weekends (96.2%), particularly in the evening (99.2%). Multivariate analyses revealed elevated odds of having active girls and boys in the target area during the afternoon and evening, particularly in organized and equipped areas, compared to the morning. Based on this information, it is worth proposing the need to promote the active use of public open spaces in the city of Rivera (Uruguay).
Assuntos
Exercício Físico , Humanos , Masculino , Adolescente , Feminino , Criança , Uruguai , Pré-Escolar , Lactente , Planejamento Ambiental , RecreaçãoRESUMO
Background/objective: Uruguay was enrolled in the fourth edition of the Global Matrix on physical activity-related indicators in children and adolescents with the aim of producing its second Report Card and analyses on the ten core indicators. Methods: A harmonized development process proposed by the Active Healthy Kids Global Alliance was followed. The best available scientific and grey literature was systematically searched for all the indicators included in the Report Card (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior, Physical Fitness, Family and Peers, School, Community and Environment, and Government). A grading scale ranging from A to F was used. A new approach was used to grade the Government indicator according to the Active Healthy Kids Global Alliance guidance. Results: New information was identified and 7 out of 10 indicators were graded, while there were 3 out of 10 indicators with incomplete information to be graded. An gender-based analysis was included in this second Report Card, providing separate grades for 5 of the indicators [girls/boys]: Overall Physical Activity [F/F], Organized Sport Participation [F/D], Active Transportation [C/C], Sedentary Behavior [D+/D+], and Community and Environment [D+/C-]. The comparison between 2018 and 2022 analysis showed a decrease in Overall Physical Activity and Organized Sport Participation, while the sources of influence School and Government obtained a higher grade in comparison with the previous Report Card. Conclusion: Uruguay has developed its second version of the Report Card on physical activity-related indicators in children and adolescents. The gender analysis showed inequalities between girls and boys. In summary, behavioral indicators have decreased while sources of influence have risen along the time.
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Background: The first Uruguay's Report Card in 2018 based on the Global Matrix initiative showed the lack of information on physical activity in children and adolescents. This study mapped and examined the available evidence on physical activity-related indicators based on Uruguay's 2022 Report Card. Methods: The scoping review was reported using the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews guidelines. A comprehensive literature search was performed for the period between 2018 and 2021, including electronic databases (PubMed, Web of Science, LILACS, Scielo, and Latindex), gray literature (Google Scholar, open access thesis, relevant websites of State-agencies and International Organizations), national and regional relevant journals, and reference lists of key texts. Two researchers independently conducted both the selection and data-charting process. Data items from each paper were charted based on the Population, Concept, and Context elements reflected in the objective of the review. A narrative synthesis and network plots were conducted to summarize the evidence. Results: A total of 20 papers were included in this review, consisting of four peer-reviewed scientific papers, three bachelor's theses, four official documents of State-agencies, four Government reports, of which three included national surveys, and five laws. Strengths, weaknesses, and knowledge gaps were identified from the available evidence. We synthesized main challenges such as publishing scientific studies, establishing cross-national and cross-sectoral collaborations in research projects, generating high-quality data, reporting information on social inequality indicators that influence equitable distribution, or increasing access to public information. Our results support early emerging and growth research on this topic. However, despite existing papers on physical activity-related indicators in Uruguayan youths, the lack of high-quality evidence remains clear. Conclusion: The findings of this scoping review provide the best available evidence for identifying and overcoming the challenges of physical activity-related indicators research in Uruguay. The methodological framework used could be useful for countries involved in future editions of the Global Matrix initiative. Systematic review registration: Open Science Framework, https://osf.io/hstbd/.
Assuntos
Exercício Físico , Adolescente , Criança , Humanos , UruguaiRESUMO
Resumen: Introducción: la medición precisa de la actividad física (AF) es clave para analizar su asociación con resultados de salud. Sin embargo, en Uruguay no existen estudios que comparen diferentes métodos para determinar la AF en adultos. El objetivo de este estudio fue analizar la confiabilidad del Cuestionario Internacional de Actividad Física (IPAQ) en estudiantes universitarios uruguayos y evaluar su validez concurrente en comparación con la AF basada en dispositivos. Método: 54 estudiantes universitarios de educación física completaron el IPAQ (versión larga) en dos ocasiones con 7 días de diferencia y utilizaron acelerómetros GeneActiv durante ese período. La confiabilidad se evaluó a través del Coeficiente de Correlación Intraclase (ICC) y se utilizó el análisis de Bland-Altman para determinar la validez concurrente. Resultados: todos los dominios de AF mostraron niveles moderados de ICC. El transporte (ICC = 0,64), el tiempo libre (ICC = 0,58), y la AF total (ICC = 0,53) fueron los dominios con niveles moderados más altos. El total de minutos de AF evaluados a través del IPAQ en las dos ocasiones reportó un promedio de 773 minutos de diferencia (IC 95% 362,88-1.184,01). La diferencia de minutos de AF entre la evaluación con el IPAQ y con los acelerómetros es de 752 minutos (IC 95% 418,05-1.087.16). Conclusiones: el IPAQ sobreestima la AF respecto al acelerómetro en estudiantes universitarios uruguayos, sin embargo fue más confiable al considerar dominios de transporte y tiempo libre para los participantes que reportaron realizar un promedio menor a 400 minutos de AF semanal.
Summary: Introduction: precise measurement of physical activity (PA) is key to analyze its association with health results. However, there are no studies in Uruguay comparing the different methods to determine PA in adults. The study aims to analyze the reliability of the International Physical Activity Questionnaire (IPAQ) in Uruguayan university students and to assess its validity by comparing it to device-based monitoring PA. Method: 54 Physical Education university students completed the IPAQ (long version) on 2 occasions with a 7 day difference using GeneActive accelerometers during that period. Reliability was assessed with the Intraclass Correlation Coefficient (ICC) and the Bland-Altman analysis was used to determine concurrent validity. Results: all PA domains evidenced moderate ICC levels. Transport (ICC= 0.64), free time (ICC= 0.58) and total PA (ICC= 0.53) were the domains with the highest moderate levels. The total number of minutes of PA assessed by IPAQ reported an average of a 773 minutes difference (CI 95%: 362.88; 1184.01). Difference of PA in minutes, considering the assessment with the IPAQ and the accelerometers is 752 minutes (CI 95%: 418.05; 1087.16). Conclusions: the IPAQ overestimates the PA when compared to the accelerometer in Uruguayan university students. However, it was more reliable when considering the transport and free time domains for participants who reported an average physical activity under 400 minutes per week.
Resumo: Introdução: a mensuração precisa da atividade física (AF) é fundamental para analisar sua associação com desfechos de saúde. No entanto, no Uruguai não existem estudos que comparem diferentes métodos para determinar a AF em adultos. Objetivo: analisar a confiabilidade do Questionário Internacional de Atividade Física (IPAQ) em estudantes universitários uruguaios e avaliar sua validade concorrente em comparação com a AF baseada em dispositivos. Método: 54 estudantes universitários de Educação Física preencheram o IPAQ (versão longa) em 2 ocasiões com 7 dias de intervalo e usaram acelerômetros GeneActiv durante esse período. A confiabilidade foi avaliada por meio do Coeficiente de Correlação Intraclasse (ICC) e a análise de Bland-Altman foi utilizada para determinar a validade concorrente. Resultados: todos os domínios da AF apresentaram níveis moderados de ICC. Transporte (ICC = 0,64), tempo livre (ICC = 0,58) e AF total (ICC = 0,53) foram os domínios com os níveis moderados mais altos. O total de minutos de AF avaliados pelo IPAQ em ambas as ocasiões apresentou diferença média de 773 minutos (IC 95%: 362,88; 1184,01). A diferença em minutos de AF entre a avaliação com o IPAQ e com os acelerômetros é de 752 minutos (IC 95%: 418,05; 1087,16). Conclusões: o IPAQ superestima a AF em relação ao acelerômetro em universitários uruguaios, porém, foi mais confiável ao considerar os domínios transporte e tempo livre para participantes que relataram realizar em média menos de 400 minutos de AF por semana.
Assuntos
Exercício Físico , Inquéritos e Questionários/estatística & dados numéricos , Estudo de AvaliaçãoRESUMO
Resumen: En la actualidad estamos viviendo una pandemia provocada por el virus del SARS-CoV-2, el COVID-19, siendo lo más recomendado quedarse en casa para disminuir el contagio y que éste se reduzca al mínimo posible. En el siglo XXI la tecnología está más presente que nunca y forma parte de nuestra vida cotidiana. Dado que existe un importante abuso de aquélla, especialmente por parte de los adolescentes, desde nuestra perspectiva promotora del movimiento y de la reducción del comportamiento sedentario, proponemos el uso de los videojuegos activos como sustitución de los videojuegos convencionales. Para ello, se han revisado los principales beneficios que éstos pueden aportar, tanto a la población más joven como a los adultos mayores. Este último grupo de edad es uno de los más afectados por la pandemia y por tanto hay una fuerte recomendación para que permanezcan en sus hogares. No obstante, se recomienda hacer un uso responsable y no invertir un tiempo excesivo que pueda conllevar perjuicios.
Summary: We are currently living the SARS CoV2, COVID-19 pandemic, the highest recommendation being to stay at home to reduce the risk of contagion and thus disease transmission to the minimum. More than ever, technology is part of our daily life in this 21st century. Given the significant abuse of technology, in particular by adolescents, and considering our perspective that is grounded on promoting movement and reducing a sedentary lifestyle, we suggest using active videogames to substitute conventional ones. To that end, we have conducted a review of the main benefits of videogames on the younger population, as well as on older adults, who constitute one of the most affected sectors by the pandemic and were consequently strongly encouraged to stay at home. However, a recommendation is made to make a responsible use of active videogames and avoid investing excessive time, what may result in a negative impact.
Resumo: No momento vivemos uma pandemia causada pelo vírus SARS-CoV-2, COVID-19, sendo o mais recomendado ficar em casa para reduzir o contágio e que este seja reduzido ao mínimo possível. No século 21, a tecnologia está mais presente do que nunca e faz parte do nosso dia a dia. Tendo em vista que há significativo abuso da mesma, principalmente por adolescentes, na nossa perspectiva que promove o movimento e a redução do comportamento sedentário, propomos o uso de videogames ativos em substituição aos videogames convencionais. Para isso, fizemos uma revisão dos principais benefícios que estas podem trazer, tanto para a população mais jovem como para os idosos. Esta última faixa etária é uma das mais afetadas pela pandemia e, portanto, há uma forte recomendação para que fiquem em casa. No entanto, é recomendável usá-lo com responsabilidade e não investir tempo excessivo que possa causar danos.
Assuntos
Adolescente , Idoso , Idoso de 80 Anos ou mais , Exercício Físico , Jogos de Vídeo , Comportamento SedentárioRESUMO
La ingestión accidental de cuerpos extraños, más frecuentemente espinas de pescado, causa perforaciones intestinales en menos del 1 % de los casos; la alta morbimortalidad asociada con estas ha favorecido la búsqueda de alternativas frente a la cirugía convencional. El caso presentado muestra cómo el abordaje combinado secuencial laparoscópico y endoscópico, permite resolver con menor grado de agresión una perforación sigmoidea por cuerpo extraño
Accidental ingestion of foreign bodies, more frequently fishbones, causes intestinal perforations in less than 1% of cases. The associated high morbidity and mortality has lead to the search for alternatives to conventional surgery. The presented case shows how sequential approach, laparoscopic and endoscopic combined, allows a sigmoid perforation by a foreign body to be solved with a lower aggressive approach
Assuntos
Humanos , Perfuração Intestinal , Colo Sigmoide , Endoscopia do Sistema Digestório , Corpos EstranhosRESUMO
OBJECTIVE: To define whether anti-ribosomal P (anti-P) autoantibodies from patients with neuropsychiatric systemic lupus erythematosus (NPSLE) impair the function of hippocampal neurons that express the neuronal surface P antigen (NSPA) when accessing the brain via circulating blood. METHODS: We used anti-P antibodies from patients with NPSLE and rabbit-generated anti-P and anti-NSPA antibodies. Primary hippocampal neurons from mice were analyzed to determine antibody cell surface binding (double immunofluorescence), intracellular calcium variations (Fura 2 AM), and apoptosis (caspase 3 activation). Hippocampal-dependent spatial flexible memory was assessed in mice subjected to a water maze test 24 hours after an intravenous injection of anti-P or anti-NSPA, using lipopolysaccharide (LPS) to permeate the blood-brain barrier. Presence of antibodies and apoptosis in the hippocampus was studied using immunohistochemistry and TUNEL assays. RESULTS: Hippocampal neurons expressed NSPA on the cell surface, as revealed by anti-P and anti-NSPA staining colocalization, and responded to both anti-P and anti-NSPA by exhibiting increased intracellular calcium levels. Neuronal apoptosis was induced when anti-P was directly injected by stereotaxis into the hippocampus or added to primary cultures. Upon LPS treatment, intravenously injected anti-P impaired memory but did not elicit neuronal apoptosis in the hippocampus, where it was detectable in low amounts. Anti-NSPA antibodies also impaired memory. CONCLUSION: Anti-P antibodies interact with NSPA on the surface of hippocampal neurons leading to apoptotic death or to functional perturbations, results that are likely dependent on the concentration of these antibodies. Circulating anti-P can access the hippocampus and impair memory without requiring neuronal death when the blood-brain barrier is disrupted. NSPA can mediate antibody-driven diffuse brain dysfunction, and anti-P might contribute to the cognitive impairment that is frequently observed in SLE.
Assuntos
Autoanticorpos/efeitos adversos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Transtornos da Memória/etiologia , Transtornos da Memória/imunologia , Proteínas Ribossômicas/imunologia , Adolescente , Animais , Antígenos de Superfície/metabolismo , Apoptose/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Ribossômicas/metabolismo , Adulto JovemRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-ß peptide (Aß), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-ß protein precursor (AßPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to assess the effect of peroxisomal proliferation on Aß neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Aß burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Química Encefálica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Proliferadores de Peroxissomos/administração & dosagem , Sinapses/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Química Encefálica/genética , Modelos Animais de Doenças , Humanos , Masculino , Transtornos da Memória/genética , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/patologia , Sinapses/patologiaRESUMO
The c-Abl tyrosine kinase is an important link in signal transduction pathways that promote cytoskeletal rearrangement and apoptotic signalling. We have previously shown that amyloid-ß-peptide (Aß) activates c-Abl. Herein we show that c-Abl participates in Aß-induced tau phosphorylation through Cdk5 activation. We found that intraperitoneal administration of STI571, a specific inhibitor for c-Abl kinase, decreased tau phosphorylation in the APPswe/PSEN1ΔE9 transgenic mouse brain. In addition, when neurons were treated with Aß we observed: (i) an increase in active c-Abl and tau phosphorylation, (ii) the prevention of tau phosphorylation by STI571 and (iii) the inhibition of c-Abl expression by shRNA, as well as the expression of a c-Abl kinase death mutant, decreased AT8 and PHF1 signals. Furthermore, the increase of c-Abl was associated with Tyr15 phosphorylation of Cdk5 and its association with c-Abl. Brains from APPswe/PSEN1ΔE9 mice showed higher levels of c-Abl and phospho-Cdk5 than wild-type mice. Moreover, STI571 treatment decreased the phospho-Cdk5 levels. Together, the evidence suggests that activation of c-Abl by Aß promotes tau phosphorylation through Tyr15 phosphorylation-mediated Cdk5 activation.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Hipocampo/enzimologia , Proteínas Proto-Oncogênicas c-abl/fisiologia , Proteínas tau/metabolismo , Proteínas tau/toxicidade , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Proteínas tau/antagonistas & inibidoresRESUMO
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of beta-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide.
Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Transdução de Sinais/fisiologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Biologia Computacional , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Cloreto de Lítio/farmacologia , Cloreto de Lítio/uso terapêutico , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Testes Neuropsicológicos , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Ratos , Ratos Endogâmicos , Fatores de Transcrição TCF/metabolismo , Transfecção , Proteínas Wnt/farmacologia , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/genéticaRESUMO
The Wnt signaling pathway has a role in several cellular processes, including cellular communication, embryonic development and cancer. Recent studies show that the Wnt pathway also has an important role in some aspects of neuronal circuit development, such as neuronal migration, synaptic differentiation, mature synapse modulation and synaptic plasticity. Wnt signaling begins during neural development and is crucial for long-term potentiation in the adult brain. The Wnt pathway may have potential in the prevention of neurodegenerative diseases that involve synaptic impairment. Several years ago our laboratory found a relationship between the loss of Wnt signaling and amyloid-beta-peptide (Abeta) neurotoxicity, which is involved in Alzheimer's disease (AD). The activation of the Wnt signaling cascade prevents Abeta-dependent cytotoxic effects. We proposed that beta-catenin-dependent Wnt ligands have a role in the modulation of presynaptic processes such as neurotransmitter release. beta-catenin-independent Wnt signaling controls the postsynaptic site, increasing the incorporation of PSD-95 and glutamatergic receptors in the postsynaptic region. This could prevent the effects of Abeta exposure at the postsynaptic level. The study of the Wnt pathway is a promising approach in the search for possible targets to fight the deleterious effects of neurodegenerative conditions such as AD.
Assuntos
Sistemas de Liberação de Medicamentos , Transdução de Sinais , Proteínas Wnt/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Sinapses/metabolismoRESUMO
In the past several years, we postulated that the loss of Wnt signaling was implicated in the pathology of Alzheimer's disease (AD). Since then, our lab and other groups have confirmed the involvement of the Wnt signaling in some aspects of AD. So far, we have demonstrated that activation of Wnt signaling protects neurons against neurotoxic injuries, including both amyloid-beta (Abeta) fibrils and Abeta oligomers by using either lithium, an inhibitor of the glycogen-synthase-kinase-3beta (GSK-3beta), or different Wnt ligands. Also, we have found that several molecules which activate well known neurotransmitter systems and other signaling system, are able by crosstalk to activate Wnt/beta-catenin signaling in order to protect neurons against both Abeta fibrils or Abeta oligomers. In particular, the activation of non-canonical Wnt signaling was able to protect postsynaptic regions and dendritic spines against Abeta oligomers. Furthermore Wnt signaling ligands also affect stem cells, and they are also involved in cell fate decision during neurogenesis and embryonic development as well as in adult stem cells differentiation in the nervous system. The Wnt signaling plays a key role modulating their cell differentiation or proliferation states. Altogether, these findings in both stem cell biology and neuroprotection, may introduce new approaches in the treatment of neurodegenerative diseases, including drug screening and therapies against neurodegenerative diseases which activates the Wnt signaling pathway.
Assuntos
Diferenciação Celular/fisiologia , Degeneração Neural/prevenção & controle , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Proteínas Wnt/fisiologia , Doença de Alzheimer/terapia , Animais , Modelos Animais de Doenças , Modelos Biológicos , Degeneração Neural/etiologiaRESUMO
Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmic levels of beta-catenin has been observed. Apparently Abeta binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/beta-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/beta-catenin signaling, including the activation of M1 muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR alpha, gamma agonists, nicotine and some antioxidants, results in neuroprotection against Abeta. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.
RESUMO
The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid-beta-peptide (Abeta). Amyloid deposits contain "chaperone molecules" which play critical roles in amyloid formation and toxicity. In the present work, we test an analog of hyperforin (IDN 5706) which releases the AChE from both the Abeta fibrils and the AChE-Abeta burdens in transgenic mice. Hyperforin is an acylphloroglucinol compound isolated from Hypericum perforatum (St. John's Wort), which is able to prevent the Abeta-induced spatial memory impairments and Abeta neurotoxicity. Altogether this gathered evidence indicates the important role of AChE in the neurotoxicity of Abeta plaques and finding new compounds which decrease the AChE-Abeta interaction may be a putative therapeutic agent to fight the disease.
Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/fisiologia , Transtornos da Memória/enzimologia , Precursor de Proteína beta-Amiloide/genética , Animais , Imuno-Histoquímica , Camundongos , Camundongos TransgênicosRESUMO
There is evidence that amyloid beta-protein (Abeta) deposits or Abeta intermediates trigger pathogenic factors in Alzheimer's disease patients. We have previously reported that c-Abl kinase activation involved in cell signalling regulates the neuronal death response to Abeta fibrils (Abeta(f)). In the present study we investigated the therapeutic potential of the selective c-Abl inhibitor STI571 on both the intrahippocampal injection of Abeta(f) and APPsw/PSEN1DeltaE9 transgenic mice Alzheimer's disease models. Injection of Abeta(f) induced an increase in the numbers of p73 and c-Abl immunoreactive cells in the hippocampal area near to the lesion. Chronic intraperitoneal administration of STI571 reduced the rat behavioural deficit induced by Abeta(f), as well as apoptosis and tau phosphorylation. Our in vitro studies suggest that inhibition of the c-Abl/p73 signalling pathway is the mechanism underlying of the effects of STI571 on Abeta-induced apoptosis for the following reasons: (i) Abeta(f) induces p73 phosphorylation, the TAp73 isoform levels increase so as to enhance its proapoptotic function, and all these effects where reduced by STI571; (ii) c-Abl kinase activity is required for neuronal apoptosis and (iii) STI571 prevents the Abeta-induced increase in the expression of apoptotic genes. Furthermore, in the Abeta-injected area there was a huge increase in phosphorylated p73 and a larger number of TAp73-positive cells, with these changes being prevented by STI571 coinjection. Moreover, the intraperitoneal administration of STI571 rescued the cognitive decline in APPsw/PSEN1DeltaE9 mice, p73 phosphorylation, tau phosphorylation and caspase-3 activation in neurons around Abeta deposits. Besides, we observed a decrease in the number and size of Abeta deposits in the APPsw/PSEN1DeltaE9-STI571-treated mice. These results are consistent with the role of the c-Abl/p73 signalling pathway in Abeta neurodegeneration, and suggest that STI571-like compounds would be effective in therapeutic treatments of Alzheimer disease.
Assuntos
Doença de Alzheimer/prevenção & controle , Apoptose/efeitos dos fármacos , Pirimidinas/uso terapêutico , Proteínas tau/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Animais , Benzamidas , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mesilato de Imatinib , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Piperazinas , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/metabolismoRESUMO
Nicotinic acetylcholine receptors (nAChRs) contribute significantly to hippocampal function. Alpha7-nAChRs are present in presynaptic sites in hippocampal neurons and may influence transmitter release, but the factors that determine their presynaptic localization are unknown. We report here that Wnt-7a, a ligand active in the canonical Wnt signaling pathway, induces dissociation of the adenomatous polyposis coli (APC) protein from the beta-catenin cytoplasmic complex and the interaction of APC with alpha7-nAChRs in hippocampal neurons. Interestingly, Wnt-7a induces the relocalization of APC to membranes, clustering of APC in neurites, and coclustering of APC with different, presynaptic protein markers. Wnt-7a also increases the number and size of coclusters of alpha7-nAChRs and APC in presynaptic terminals. These short-term changes in alpha7-nAChRs occur in the few minutes after ligand exposure and involve translocation to the plasma membrane without affecting total receptor levels. Longer-term exposure to Wnt-7a increases nAChR alpha7 subunit levels in an APC-independent manner and increases clusters of alpha7-nAChRs in neurites via an APC-dependent process. Together, these results demonstrate that stimulation through the canonical Wnt pathway regulates the presynaptic localization of APC and alpha7-nAChRs with APC serving as an intermediary in the alpha7-nAChR relocalization process. Modulation by Wnt signaling may be essential for alpha7-nAChR expression and function in synapses.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Terminações Pré-Sinápticas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Receptores Nicotínicos/metabolismo , Proteínas Wnt/fisiologia , Animais , Linhagem Celular , Células Cultivadas , Hipocampo/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/química , Terminações Pré-Sinápticas/química , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/fisiologia , Transdução de Sinais/fisiologia , Receptor Nicotínico de Acetilcolina alfa7 , beta Catenina/metabolismoRESUMO
Prion diseases are fatal neurodegenerative disorders associated with the conversion of the cellular prion protein (PrPC) into a pathologic isoform. Although the physiological function of PrPC remains unknown, evidence relates PrPC to copper metabolism and oxidative stress as suggested by its copper-binding properties in the N-terminal octapeptide repeat region. This region also reduces copper ions in vitro, and this reduction ability is associated with the neuroprotection exerted by the octarepeat region against copper in vivo. In addition, the promoter region of the PrPC gene contains putative metal response elements suggesting it may be regulated by heavy metals. Here we address some of the evidence that support a physiological link between PrPC and copper. Also, in vivo experiments suggesting the physiological relevance of PrPC interaction with heparan sulfate proteoglycans are discussed.
Assuntos
Cobre/metabolismo , Estresse Oxidativo/fisiologia , Proteínas PrPC/metabolismo , Animais , Proteoglicanas de Heparan Sulfato/metabolismo , Proteínas PrPC/genética , Doenças Priônicas/metabolismo , Ligação Proteica , RatosRESUMO
Prion diseases are caused by the conformational transition of the native alpha-helical cellular prion protein (PrPC) into a beta-sheet pathogenic isoform. However, the normal physiological function of PrPC remains elusive. We report herein that copper induces PrPC expression in primary hippocampal and cortical neurons. PrPC induced by copper has a normal glycosylation pattern, is proteinase K-sensitive and reaches the cell surface attached by a glycosyl phosphatidylinositol anchor. Immunofluorescence analysis revealed that copper induces PrPC levels in the cell surface and in an intracellular compartment that we identified as the Golgi complex. In addition, copper induced the activity of a reporter vector driven by the rat PrPC gene (Prnp) promoter stably transfected into PC12 cells, whereas no effect was observed in glial C6 clones. Also cadmium, but not zinc or manganese, upregulated Prnp promoter activity in PC12 clones. Progressive deletions of the promoter revealed that the region essential for copper modulation contains a putative metal responsive element. Although electrophoretic mobility shift assay demonstrated nuclear protein binding to this element, supershift analysis showed that this is not a binding site for the metal responsive transcription factor-1 (MTF-1). The MTF-1-independent transcriptional activation of Prnp is supported by the lack of Prnp promoter activation by zinc. These findings demonstrate that Prnp expression is upregulated by copper in neuronal cells by an MTF-1-independent mechanism, and suggest a metal-specific modulation of Prnp in neurons.
Assuntos
Amiloide/genética , Amiloide/metabolismo , Cobre/metabolismo , Neurônios/fisiologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/citologia , Cobre/farmacologia , Proteínas de Ligação a DNA/metabolismo , Detergentes , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Homeostase/fisiologia , Neurônios/citologia , Príons , Regiões Promotoras Genéticas/fisiologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Fatores de Transcrição/metabolismo , Fator MTF-1 de TranscriçãoRESUMO
Prion diseases are fatal neurodegenerative disorders associated with the conversion of the cellular prion protein (PrPC) into a pathologic isoform. Although the physiological function of PrPC remains unknown, evidence relates PrPC to copper metabolism and oxidative stress as suggested by its copper-binding properties in the N-terminal octapeptide repeat region. This region also reduces copper ions in vitro, and this reduction ability is associated with the neuroprotection exerted by the octarepeat region against copper in vivo. In addition, the promoter region of the PrPC gene contains putative metal response elements suggesting it may be regulated by heavy metals. Here we address some of the evidence that support a physiological link between PrPC and copper. Also, in vivo experiments suggesting the physiological relevance of PrPC interaction with heparan sulfate proteoglycans are discussed.