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In environments teeming with distractions, the ability to selectively focus on relevant information is crucial for advanced cognitive processing. Existing research using event-related potential (ERP) technology has shown active suppression of irrelevant stimuli during the consolidation phase of visual working memory (VWM). In previous studies, participants have always been given sufficient time to consolidate VWM, while suppressing distracting information. However, it remains unclear whether the suppression of irrelevant distractors requires continuous effort throughout their presence or whether this suppression is only necessary after the consolidation of task-relevant information. To address this question, our study examines whether distractor suppression is necessary in scenarios where consolidation time is limited. This research investigates the effect of varying presentation durations on the filtering of distractors in VWM. We tasked participants with memorizing two color stimuli and ignoring four distractors, presented for either 50 ms or 200 ms. Using ERP technology, we discovered that the distractor-induced distractor positivity (PD) amplitude is larger during longer presentation durations compared to shorter ones. These findings underscore the significant impact of presentation duration on the efficacy of distractor suppression in VWM, as prolonged exposure results in a stronger suppression effect on distractors. This study sheds light on the temporal dynamics of attention and memory, emphasizing the critical role of stimulus timing in cognitive tasks. These findings provide valuable insights into the mechanisms underlying VWM and have significant implications for models of attention and memory.
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Atención , Electroencefalografía , Potenciales Evocados , Memoria a Corto Plazo , Percepción Visual , Humanos , Memoria a Corto Plazo/fisiología , Atención/fisiología , Masculino , Femenino , Potenciales Evocados/fisiología , Adulto Joven , Adulto , Percepción Visual/fisiología , Factores de Tiempo , Estimulación LuminosaRESUMEN
Circular RNAs (circRNAs) have been recognized as pivotal regulators in tumorigenesis, yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma (HCC) remain elusive. We sought to unveil the expression profile and biological role of circMYBL2 in HCC. Initial microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells, and qRTâPCR analysis was then performed in HCC cell lines and tissues, revealing significant upregulation of circMYBL2. Subsequent experiments were conducted to evaluate the biological function of circMYBL2 in HCC progression. Furthermore, bioinformatics analysis, qRTâPCR analysis, luciferase reporter assays, and western blot analysis were employed to investigate the interplay among circMYBL2, miR-1205, and E2F1. CircMYBL2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell lines. Elevated expression of circMYBL2 increased the proliferation and migration of HCC cells, whereas circMYBL2 knockdown elicited contrasting effects. Mechanistically, our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging miR-1205. Our findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis, suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.
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Carcinoma Hepatocelular , Progresión de la Enfermedad , Factor de Transcripción E2F1 , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , ARN Circular , Humanos , Ratones , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Pronóstico , ARN Circular/genéticaRESUMEN
This research aims to elucidate the relationship between circular design strategies (CDS) and the economic sustainability of construction projects (ESCP), examining the mediating role of organizational culture (OC). Motivated by the imperative to develop a sustainable circular economy (CE) model in the building industry, our study focuses on a crucial dimension of CE processes. Specifically, we investigate how construction firms' organizational values shape their pursuit of desired economic outcomes within CE theory. Through a comprehensive analysis of 359 responses from a cross-sectional survey of Chinese construction firms employing Partial Least Squares-Structural Equation Modeling (PLS-SEM), our findings reveal a positive albeit weakly impactful association between CDS and ESCP. Simultaneously, OC is identified as a factor detrimental to ESCP. Notably, this study unveils the influential roles of hierarchical culture (HC) and group culture (GC) in shaping the current state of ESCP in China. Emphasizing the significance of CDS, we propose that contract administrators proactively reposition their organizations to adopt strategies conducive to achieving the necessary economic output for construction projects. The originality aspect lies in this research contributes to the existing body of knowledge by offering empirical insights into the theoretical framework, marking the first such empirical study in northern China. We conclude by critically examining research outcomes and limitations while providing insightful recommendations for future research to foster sustainable construction practices in the Chinese context.
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CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key "molecular switch" in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.
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Wnt signaling pathway activation is involved in the pathogenesis of a series of malignant tumors and is characterized by the nuclear accumulation of ß-catenin protein. The occurrence of two or more Wnt pathway-associated tumors in a single individual is uncommon and generally attributed to inherited cancer syndrome, especially familial adenomatous polyposis (FAP). Herein, we presented a rare case of a child who suffered from the occurrence of Wnt-activated medulloblastoma and cribriform-morular thyroid carcinoma (CMTC) within a 9-year interval. She had no history of FAP and harbored an unexpected somatic mutation of the APC gene in the CMTC tumor. The potential agents involved in the pathogenesis of the two molecular-linked tumors other than FAP were discussed in this report.
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Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.
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ADP-Ribosilación , Neoplasias , Roturas del ADN de Doble Cadena , Daño del ADN , Reparación del ADN , Neoplasias/genética , Neoplasias/radioterapia , Poli(ADP-Ribosa) Polimerasa-1/genética , Procesamiento Proteico-Postraduccional , Humanos , Línea Celular , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Histona Metiltransferasas/genética , Histona Metiltransferasas/metabolismoRESUMEN
OBJECTIVES: To evaluate the role of rapid immunohistochemistry (RIHC) based on ultrasonic thermal steam heating in improving diagnostic accuracy of intraoperative frozen section diagnosis and to recommend RIHC antibody panels for pathologic differential diagnosis. MATERIALS AND METHODS: RIHC based on ultrasonic thermal steam heating was tested for intraoperative frozen diagnosis with difficulty in diagnosis, and all slides were reviewed and compared with the final diagnosis. Ninety-three cases of surgical specimens involving RIHC examination were studied. Discordance rates with paraffin immunohistochemistry were calculated. RESULTS: In 93 cases where RIHC was performed, 85 cases (91%) were proven to be helpful for the diagnosis. A total of 58 antibodies were used for RIHC 276 times, of which 19 antibodies were not effective 25 times. Fifteen RIHC antibody panels are recommended based on staining stability and utilization frequency. CONCLUSION: After improving the staining method, ultrasonic thermal steam heating RIHC is practical, convenient, and cost-effective, making it suitable for use in any pathology department with routine immunohistochemistry reagents. It plays an important auxiliary role in improving the accuracy of intraoperative rapid pathologic diagnosis.
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Vapor , Ultrasonido , Humanos , Inmunohistoquímica , Calefacción , Diagnóstico DiferencialRESUMEN
The stroma-rich variant of Castleman disease of hyaline-vascular type (SR-HVCD) is characterized by interfollicular proliferation of the fibroblastic, myofibroblastic, and/or histiocytic-derived stromal cells, occurred in a background of Castleman disease of hyaline-vascular type (HVCD). It has been considered as a hyperplastic disorder by far. Herein, we presented a case of a 40-year-old male suffering from an occupation in the right middle mediastinum. Microscopically, the lesion was characterized by atretic lymphoid follicles and overgrowth of the interfollicular spindle-shaped cells. Those spindle cells were histologically bland in some areas, while exhibited notable cellular atypia and focal necrosis in other areas. SMA and CD68 were immunostained with a subset of the spindle cells in both areas, whereas p53 staining was only perceived in areas with markedly cellular atypia. In addition, indolent T-lymphoblastic proliferation (iT-LBP) was present inside the lesion. The patient developed multiple sites metastases 4 months after surgery, and succumbed to the disease at 7 months. Our case demonstrates for the first time that SR-HVCD have a tumorigenesis potential rather than a simple hyperplastic process. Such disorder should be carefully evaluated to avoid underdiagnosis.
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Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.
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Enfermedad de Alzheimer , Tauopatías , Animales , Ratones , Sirtuina 1/genética , Sirtuina 1/metabolismo , Tauopatías/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Fosforilación , Encéfalo/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by two pathological features: neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-ß (Aß). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.
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Private science and technology enterprises are the main force in building a high-level innovative province in Zhejiang, and are also the driving force for the province's high-quality integration into the Yangtze River Delta. At present, the integration of private science and technology enterprises in Zhejiang into the Yangtze River Delta has problems such as low integration ratio, high integration difficulty, low integration level, and insufficient integration confidence. The causes of the problem mainly include the concept bottlenecks and capacity limitations of private technology companies, the institutional dilemma of cooperation between regional governments and regional business environment synergy is not high, the role of non-governmental organizations is not fully developed. To create a powerful engine that drives private technology enterprises to deeply participate in the development of the Yangtze River Delta, it should be built and strengthened from the perspective of the main role of enterprises themselves, the role of government guidance, industry associations, and other non-governmental organizations to play the role of service coordination and supervision.
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Industrias , Ríos , China , Comercio , TecnologíaRESUMEN
BACKGROUND: Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer's disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD. OBJECTIVE: The present study investigated the association between SIRT1 and tau expression/tau localization in cells and in mice brains. METHODS: Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains. RESULTS: In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/- mice. CONCLUSION: SIRT1 may be a potential drug target for early intervention in AD.
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Sirtuina 1/metabolismo , Transmisión Sináptica/fisiología , Tauopatías/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Ratones , Ratones Noqueados , Ovillos Neurofibrilares , Sirtuina 1/genéticaRESUMEN
The abnormal accumulation of amyloid-b (Ab) and neurofibrillary tangles (NFTs) containing phosphorylated tau proteins are the main histopathological feature of Alzheimer's disease (AD). Synaptic damage and loss are earlier events than amyloid plaques and NFTs in AD progress and best correlate with cognitive deficits in AD patients. Soluble oligomeric Aß initiates the progression of AD and tau mediates the subsequent synaptic impairments at an early stage of AD. In this review we discuss how Ab or/and tau causes synaptic dysfunction. Ab oligomers gather at synapses and give rise to synaptic death in a variety of ways such as regulating receptors and receptor tyrosine kinases, unbalancing calcium homeostasis, and activating caspases and calcineurin. A large amount of hyperphosphorylated tau exists in the synapse of the AD brain. Aß-triggered synaptic deficits are dependent on tau. Soluble, hyperphosphorylated tau is much more correlated to cognitive decline in AD patients. Tau-targeted therapies have received more attention because the treatments targeting Aß failed in AD. Here, we also review the therapy strategies used to intervene in the very early stages of AD. Soluble hyperphosphorylated tau forms a complex with cell surface receptors, scaffold proteins, or intracellular signaling molecules to damage synaptic function. Therefore, therapeutic strategies targeting synaptic tau at the early stage of AD may ameliorating pathology in AD. This review aims to provide an update on the role of oligomeric Ab and soluble hyperphosphorylated tau in the early pathogenesis of Alzheimer's disease and to develop a new treatment strategy based on this.
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Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/metabolismo , Sinapsis , Proteínas tau/metabolismo , Animales , HumanosRESUMEN
Microtubule-associated protein tau forms insoluble neurofibrillary tangles (NFTs), which is one of the major histopathological hallmarks of Alzheimer's disease (AD). Many studies have demonstrated that tau causes early functional deficits prior to the formation of neurofibrillary aggregates. The redistribution of tau from axons to the somatodendritic compartment of neurons and dendritic spines causes synaptic impairment, and then leads to the loss of synaptic contacts that correlates better with cognitive deficits than amyloid-ß (Aß) aggregates do in AD patients. In this review, we discuss the underlying mechanisms by which tau is mislocalized to dendritic spines and contributes to synaptic dysfunction in AD. We also discuss the synergistic effects of tau and oligomeric forms of Aß on promoting synaptic dysfunction in AD.
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Wild species of Gossypium ssp. are an important source of traits for improving commercial cotton cultivars. Previous reports show that Gossypium herbaceum L. and Gossypium nelsonii Fryx. have better disease resistance characteristics than commercial cotton varieties. However, chromosome ploidy and biological isolation make it difficult to hybridize diploid species with the tetraploid Gossypium hirsutum L. We developed a new allotetraploid cotton genotype (A1A1G3G3) using a process of distant hybridization within wild cotton species to create new germplasms. First of all, G. herbaceum and G. nelsonii were used for interspecific hybridization to obtain F1 generation. Afterwards, apical meristems of the F1 diploid cotton plants were treated with colchicine to induce chromosome doubling. The new interspecific F1 hybrid and S1 cotton plants originated from chromosome duplication, were tested via morphological and molecular markers and confirmed their tetraploidy through flowrometric and cytological identification. The S1 tetraploid cotton plants was crossed with a TM-1 line and fertile hybrid offspring were obtained. These S2 offsprings were tested for resistance to Verticillium wilt and demonstrated adequate tolerance to this fungi. The results shows that the new S1 cotton line could be used as parental material for hybridization with G. hirsutum to produce pathogen-resistant cotton hybrids. This new S1 allotetraploid genotype will contributes to the enrichment of Gossypium germplasm resources and is expected to be valuable in polyploidy evolutionary studies.
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Resistencia a la Enfermedad/genética , Gossypium/anatomía & histología , Gossypium/genética , Fitomejoramiento , Poliploidía , Segregación Cromosómica/genética , Cromosomas de las Plantas/genética , Fibra de Algodón , Cruzamientos Genéticos , ADN de Plantas/genética , Fertilidad , Flores/anatomía & histología , Genotipo , Gossypium/microbiología , Repeticiones de Microsatélite/genética , Especificidad de Órganos , Ploidias , Carácter Cuantitativo Heredable , Reproducibilidad de los Resultados , Verticillium/fisiologíaRESUMEN
Tau is modified with O-GlcNAcylation extensively in human brain. The O-GlcNAcylation levels of tau are decreased in Alzheimer's disease (AD) brain. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins including transcriptional factors and associates with neurodegenerative diseases, such as AD. Aberrant SIRT1 expression levels in AD brain is in parallel with the accumulation of tau. cAMP response element binding protein (CREB), a cellular transcription factor, plays a critical role in learning and memory. In this present study, we found SIRT1 deacetylates CREB and inhibits phosphorylation of CREB at Ser133. The inactivated CREB suppresses OGT expression and therefore decreases the O-GlcNAcylation of tau and thus increases the phosphorylation of tau at specific sites. These findings suggest that SIRT1 may be a potential therapeutic target for treating tauopathies.
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Acetilglucosamina/metabolismo , N-Acetilglucosaminiltransferasas/fisiología , Sirtuina 1/fisiología , Proteínas tau/metabolismo , Animales , Células COS , Chlorocebus aethiops , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Glicosilación , Células HEK293 , Humanos , N-Acetilglucosaminiltransferasas/genética , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
As the number of hepatitis hydropericardium syndrome (HHS) cases has increased in recent years in China, development of a safe and effective vaccine is now urgent. To address this problem a subunit vaccine is a good option, we here systematically investigated the minimum immune dose of a subunit vaccine against HHS based on recombinant fowl adenovirus serotype 4 (FAdV-4) fiber-2 protein and compared the effects between this subunit vaccine and an inactivated oil-emulsion FAdV-4 vaccine in a vaccination trial. The results revealed that the lowest dose of recombinant fiber-2 protein that could provide 100% protection against challenge with virulent FAdV-4 strain HB1501 as well as elicit protective immunity was 2.5⯵g/bird. Neither clinical signs nor gross lesions were observed in chickens. In addition, immunization of specific-pathogen-free (SPF) chickens with recombinant fiber-2 protein (≥2.5⯵g/bird) could induce quicker and stronger immune responses than the inactivated oil-emulsion FAdV-4 vaccine. These findings provide important information about the development of subunit vaccines for the control of HHS.
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Infecciones por Adenoviridae/inmunología , Aviadenovirus/inmunología , Proteínas de la Cápside/inmunología , Enfermedades de las Aves de Corral/inmunología , Vacunas de Subunidad/inmunología , Vacunas Virales/inmunología , Infecciones por Adenoviridae/prevención & control , Infecciones por Adenoviridae/veterinaria , Infecciones por Adenoviridae/virología , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Aviadenovirus/clasificación , Aviadenovirus/genética , Proteínas de la Cápside/genética , Pollos/virología , Enfermedades de las Aves de Corral/prevención & control , Enfermedades de las Aves de Corral/virología , Vacunas de Subunidad/química , Vacunas Virales/químicaRESUMEN
Approximately equal amounts of 3R-tau and 4R-tau resulting from alternative splicing of tau exon 10 is necessary to maintain normal brain function. Dysregulation of alternative splicing of tau exon 10 and the imbalance of 3R-tau/4R-tau have been seen in inherited and sporadic tauopathies. Splicing factor SC35 (also name as SRSF2) plays an important role in promoting tau exon 10 inclusion. SC35 is post-translationally modified by phosphorylation and acetylation, but the role of acetylation in SC35-medicated tau exon 10 inclusion is unknown. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins and associates with age-related disease such as Alzheimer's disease. In the present study, we determined the role of SIRT1 in SC35 acetylation and in the alternative splicing of tau exon 10. We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing.
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Enfermedad de Alzheimer/metabolismo , Ribonucleoproteínas/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Sirtuina 1/metabolismo , Proteínas tau/metabolismo , Empalme Alternativo , Enfermedad de Alzheimer/patología , Exones , Células HEK293 , Células HeLa , Humanos , Fosforilación , Factores de Empalme Serina-Arginina/genética , Sirtuina 1/genética , Tauopatías/metabolismo , Proteínas tau/genéticaRESUMEN
Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aß) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3ß pathway. We found GSK3ß increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3ß signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment.
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Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Glucósidos/administración & dosificación , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína Oncogénica v-akt/metabolismo , Estilbenos/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Células HEK293 , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/fisiología , Ratones , Ratones TransgénicosRESUMEN
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10. In the present study, we investigated the regulation of endogenous tau exon 10 splicing by Dyrk1A. We found that inhibition of Dyrk1A enhanced tau exon 10 inclusion, leading to an increase in 4R-tau/3R-tau ratio in differentiated-human neuronal progenitors and in the neonatal rat brains. Accompanied with overexpression of Dyrk1A, 3R-tau was increased and 4R-tau was decreased in the neonatal brains of Ts65Dn mice, a model of Down syndrome. Treatment with Dyrk1A inhibitor, green tea flavonol epigallocatechin-gallate (EGCG), from gestation to adulthood suppressed 3R-tau expression and rescued anxiety and memory deficits in Ts65Dn mouse brains. Thus, Dyrk1A might be an ideal therapeutic target for Alzheimer's disease, especially for Down syndrome and EGCG which inhibits Dyrk1A may have potential effect on the treatment or prevention of this disease.