RESUMEN
Polarized trafficking of synaptic proteins to axons and dendrites is crucial to neuronal function. Through forward genetic analysis in C. elegans, we identified a cyclin (CYY-1) and a cyclin-dependent Pctaire kinase (PCT-1) necessary for targeting presynaptic components to the axon. Another cyclin-dependent kinase, CDK-5, and its activator p35, act in parallel to and partially redundantly with the CYY-1/PCT-1 pathway. Synaptic vesicles and active zone proteins mostly mislocalize to dendrites in animals defective for both PCT-1 and CDK-5 pathways. Unlike the kinesin-3 motor, unc-104/Kif1a mutant, cyy-1 cdk-5 double mutants have no reduction in anterogradely moving synaptic vesicle precursors (SVPs) as observed by dynamic imaging. Instead, the number of retrogradely moving SVPs is dramatically increased. Furthermore, this mislocalization defect is suppressed by disrupting the retrograde motor, the cytoplasmic dynein complex. Thus, PCT-1 and CDK-5 pathways direct polarized trafficking of presynaptic components by inhibiting dynein-mediated retrograde transport and setting the balance between anterograde and retrograde motors.
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Proteínas de Caenorhabditis elegans/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Sinapsis/metabolismo , Animales , Axones , Caenorhabditis elegans , Ciclinas/metabolismo , Cinesinas/metabolismo , Neuronas , Transducción de SeñalRESUMEN
INTRODUCTION: Current physical activity guidelines recommend 150 min of moderate-to-vigorous physical activity (MVPA) for health benefits, regardless of the pattern of MVPA. However, MVPA that occurs in sessions (MVPA-S) may have different health implications compared to MVPA that is not accumulated in sessions (MVPA-nonS). This study aimed to investigate the associations of MVPA-S and MVPA-nonS with mortality. METHODS: We conducted a cohort study of the National Health and Nutrition Examination Survey 2003-2006 (n = 5,658) with accelerometer-measured physical activity at baseline and mortality followed through December 31, 2019. A session was defined as a time window of 30 min or longer where the average intensity was at or above 2020 counts/minute. MVPA accumulated within such sessions was quantified as MVPA-S, while MVPA accumulated outside the sessions was quantified as MVPA-nonS. We examined the joint association of MVPA-S and MVPA-nonS by classifying the participants into four groups (both < 75 min/week [referent], MVPA-S ≥ 75 and MVPA-nonS < 75, MVPA-S < 75 and MVPA-nonS ≥ 75, and both ≥ 75). We used 75 min as the cut-point because it is half of the guideline-recommended MVPA volume where a strong MVPA-mortality association has been observed in previous studies, and because it was close to the median of MVPA-nonS (75 min/week was the 54th percentile), allowing a sufficient sample size in each group for testing statistical significance. The hazard ratios and 95% confidence intervals were estimated with adjustment for important confounders. RESULTS: During 13.9 years of follow-up (74,988 person-years), there were 1,424 deaths, out of which 472 were related to cardiovascular diseases (CVD). Compared to the referent combination (both < 75), the hazard ratios in the other three combinations were 0.48 (0.33-0.69), 0.85 (0.71-1.01), and 0.45 (0.30-0.67) for all-cause mortality; and were 0.34 (0.17-0.70), 0.96 (0.69-1.33), and 0.40 (0.17-0.90) for CVD mortality, respectively. Results were largely consistent in the spline-based models, age- and sex-stratified analyses, complete-case analysis, competing risk analysis, and the analysis excluding deaths within two years of follow-up. CONCLUSION: In conclusion, MVPA accumulated in sessions that lasted at least 30 min was associated with significant reductions in all-cause and CVD-specific mortality risks. The health implications of MVPA that were not accumulated in such sessions warrant further investigation.
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Acelerometría , Ejercicio Físico , Encuestas Nutricionales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Mortalidad , Estudios de Cohortes , Anciano , Factores de TiempoRESUMEN
Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.
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Astrocitos/metabolismo , Región CA1 Hipocampal/metabolismo , Interleucina-33/metabolismo , Plasticidad Neuronal , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Homólogo 4 de la Proteína Discs Large/metabolismo , Técnicas de Inactivación de Genes , Hipocampo/metabolismo , Homeostasis , Interleucina-33/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas , Sinapsis/efectos de los fármacos , Sinapsis/genética , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. HIGHLIGHTS: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Transcriptoma , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , BiomarcadoresRESUMEN
INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Etnicidad , Biomarcadores , Péptidos beta-Amiloides , Proteínas tau , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patologíaRESUMEN
Microglia maintain brain homeostasis through their ability to survey and phagocytose danger-associated molecular patterns (DAMPs). In Alzheimer's disease (AD), microglial phagocytic clearance regulates the turnover of neurotoxic DAMPs including amyloid beta (Aß) and hyperphosphorylated tau. To mediate DAMP clearance, microglia express a repertoire of surface receptors to sense DAMPs; the activation of these receptors subsequently triggers a chemotaxis-to-phagocytosis functional transition in microglia. Therefore, the interaction between microglial receptors and DAMPs plays a critical role in controlling microglial DAMP clearance and AD pathogenesis. However, there is no comprehensive overview on how microglial sensome receptors interact with DAMPs and regulate various microglial functions, including chemotaxis and phagocytosis. In this review, we discuss the important axes of receptor-ligand interaction that control different microglial functions and their roles in AD pathogenesis. First, we summarize how the accumulation and structural changes of DAMPs trigger microglial functional impairment, including impaired DAMP clearance and aberrant synaptic pruning, in AD. Then, we discuss the important receptor-ligand axes that restore microglial DAMP clearance in AD and aging. These findings suggest that targeting microglial chemotaxis-the first critical step of the microglial chemotaxis-to-phagocytosis state transition-can promote microglial DAMP clearance in AD. Thus, our review highlights the importance of microglial chemotaxis in promoting microglial clearance activity in AD. Further detailed investigations are essential to identify the molecular machinery that controls microglial chemotaxis in AD.
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Enfermedad de Alzheimer , Humanos , Microglía , Péptidos beta-Amiloides , Quimiotaxis , LigandosRESUMEN
Alzheimer's disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e., EGFL7, FLT1, and VWF) and antigen-presentation machinery (i.e., B2M and HLA-E). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.
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Enfermedad de Alzheimer/genética , Núcleo Celular/genética , Células Endoteliales/metabolismo , Neuroglía/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Células Endoteliales/citología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Neuroglía/citología , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Análisis de la Célula Individual , TranscriptomaRESUMEN
BACKGROUND: Family history (FamH) of type 2 diabetes might indicate shared genotypes, environments, and/or behaviors. We hypothesize that FamH interacts with unhealthy behaviors to increase the risk of early onset of diabetes and poor cardiometabolic control. METHODS: In a cross-sectional analysis of the prospective Joint Asia Diabetes Evaluation Register including patients from 427 clinics in 11 Asian countries/regions in 2007-2021, we defined positive FamH as affected parents/siblings and self-management as (1) healthy lifestyles (balanced diet, non-use of alcohol and tobacco, regular physical activity) and (2) regular self-monitoring of blood glucose (SMBG). RESULTS: Among 86,931 patients with type 2 diabetes (mean±SD age: 56.6±11.6 years; age at diagnosis of diabetes: 49.8±10.5 years), the prevalence of FamH ranged from 39.1% to 85.3% in different areas with FamH affecting mother being most common (32.5%). The FamH group (n=51,705; 59.5%) was diagnosed 4.6 years earlier than the non-FamH group [mean (95% CI): 47.9 (47.8-48.0) vs. 52.5 (52.4-52.6), logrank p<0.001]. In the FamH group, patients with both parents affected had the earliest age at diagnosis [44.6 (44.5-44.8)], followed by affected single parent [47.7 (47.6-47.8)] and affected siblings only [51.5 (51.3-51.7), logrank p<0.001]. The FamH plus ≥2 healthy lifestyle group had similar age at diagnosis [48.2 (48.1-48.3)] as the non-FamH plus <2 healthy lifestyle group [50.1 (49.8-50.5)]. The FamH group with affected parents had higher odds of hyperglycemia, hypertension, and dyslipidemia than the FamH group with affected siblings, with the lowest odds in the non-FamH group. Self-management (healthy lifestyles plus SMBG) was associated with higher odds of attaining HbA1c<7%, blood pressure<130/80mmHg, and LDL-C<2.6 mmol/L especially in the FamH group (FamH×self-management, pinteraction=0.050-0.001). CONCLUSIONS: In Asia, FamH was common and associated with young age of diagnosis which might be delayed by healthy lifestyle while self management was associated with better control of cardiometabolic risk factors especially in those with FamH.
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Diabetes Mellitus Tipo 2 , Hipertensión , Automanejo , Anciano , Asia/epidemiología , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Hipertensión/complicaciones , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Genetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer's disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome-IL-1ß, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.
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Enfermedad de Alzheimer/metabolismo , Citocinas/metabolismo , Microglía/metabolismo , Transducción de Señal/fisiología , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Inflamasomas/metabolismoRESUMEN
Adult hippocampal neurogenesis involves the lifelong generation of neurons. The process depends on the homeostasis of the production of neurons and maintenance of the adult neural stem cell (NSC) pool. Here, we report that α2-chimaerin, a Rho GTPase-activating protein, is essential for NSC homeostasis in adult hippocampal neurogenesis. Conditional deletion of α2-chimaerin in adult NSCs resulted in the premature differentiation of NSCs into intermediate progenitor cells (IPCs), which ultimately depleted the NSC pool and impaired neuron generation. Single-cell RNA sequencing and pseudotime analyses revealed that α2-chimaerin-conditional knockout (α2-CKO) mice lacked a unique NSC subpopulation, termed Klotho-expressing NSCs, during the transition of NSCs to IPCs. Furthermore, α2-CKO led to defects in hippocampal synaptic plasticity and anxiety/depression-like behaviors in mice. Our findings collectively demonstrate that α2-chimaerin plays an essential role in adult hippocampal NSC homeostasis to maintain proper brain function.
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Proteínas Quimerinas/fisiología , Activadores de GTP Fosfohidrolasa/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Animales , Diferenciación Celular , Técnicas de Silenciamiento del Gen , Hipocampo/fisiología , Homeostasis , Ratones , Ratones Noqueados , Células-Madre Neurales/fisiología , Células Madre/fisiologíaRESUMEN
INTRODUCTION: Blood proteins are emerging as candidate biomarkers for Alzheimer's disease (AD). We systematically profiled the plasma proteome to identify novel AD blood biomarkers and develop a high-performance, blood-based test for AD. METHODS: We quantified 1160 plasma proteins in a Hong Kong Chinese cohort by high-throughput proximity extension assay and validated the results in an independent cohort. In subgroup analyses, plasma biomarkers for amyloid, tau, phosphorylated tau, and neurodegeneration were used as endophenotypes of AD. RESULTS: We identified 429 proteins that were dysregulated in AD plasma. We selected 19 "hub proteins" representative of the AD plasma protein profile, which formed the basis of a scoring system that accurately classified clinical AD (area under the curve = 0.9690-0.9816) and associated endophenotypes. Moreover, specific hub proteins exhibit disease stage-dependent dysregulation, which can delineate AD stages. DISCUSSION: This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Tamizaje Masivo , Proteómica , Proteínas tau/sangre , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Estudios de Cohortes , Endofenotipos , Hong Kong , Humanos , Persona de Mediana Edad , Fosforilación , Reproducibilidad de los ResultadosRESUMEN
Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
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Enfermedad de Alzheimer/genética , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , China , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Sistema Inmunológico/inmunología , Masculino , Persona de Mediana Edad , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/inmunología , Factores de RiesgoRESUMEN
BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.
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Prestación Integrada de Atención de Salud/estadística & datos numéricos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Adulto , Estudios de Cohortes , Femenino , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Modelos de Riesgos Proporcionales , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Autocuidado/métodos , Resultado del TratamientoRESUMEN
The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.
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Quinasa 5 Dependiente de la Ciclina/metabolismo , Dendritas/metabolismo , Proteínas/metabolismo , Sinapsis/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Homólogo 4 de la Proteína Discs Large/metabolismo , Ratones , Fosforilación/fisiología , RatasRESUMEN
BACKGROUND: Early detection and risk factor control prevent chronic kidney disease (CKD) progression. Evaluation of peripheral autonomic dysfunction may detect incident cardiovascular-renal events in type 2 diabetes (T2D). METHODS: SUDOSCAN, a non-invasive tool, provides an age-adjusted electrochemical skin conductance (ESC) composite score incorporating hands/feet ESC measurements, with a score ≤53 indicating sudomotor dysfunction. A consecutive cohort of 2833 Chinese adults underwent structured diabetes assessment in 2012-13; 2028 participants without preexisting cardiovascular disease (CVD) and CKD were monitored for incident cardiovascular-renal events until 2015. RESULTS: In this prospective cohort {mean age 57.0 [standard deviation (SD) 10.0] years; median T2D duration 7.0 [interquartile range (IQR) 3.0-13.0] years; 56.1% men; 72.5% never-smokers; baseline ESC composite score 60.7 (SD 14.5)}, 163 (8.0%) and 25 (1.2%) participants developed incident CKD and CVD, respectively, after 2.3 years of follow-up. The adjusted hazard ratios (aHRs) per 1-unit decrease in the ESC composite score for incident CKD, CVD and all-cause death were 1.02 [95% confidence interval (CI) 1.01-1.04], 1.04 (1.00-1.07) and 1.04 (1.00-1.08), respectively. Compared with participants with an ESC composite score >53, those with a score ≤53 had an aHR of 1.56 (95% CI 1.09-2.23) for CKD and 3.11 (95% CI 1.27-7.62) for CVD, independent of common risk markers. When added to clinical variables (sex and duration of diabetes), the ESC composite score improved discrimination of all outcomes with appropriate reclassification of CKD risk. CONCLUSIONS: A low ESC composite score independently predicts incident cardiovascular-renal events and death in T2D, which may improve the screening strategy for early intervention.
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Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/diagnóstico , Mortalidad , Insuficiencia Renal Crónica/fisiopatología , Piel/patología , Adolescente , Adulto , Anciano , Área Bajo la Curva , Asia/epidemiología , Pueblo Asiatico , Enfermedades Cardiovasculares/complicaciones , Niño , Preescolar , Neuropatías Diabéticas/complicaciones , Progresión de la Enfermedad , Conductividad Eléctrica , Electroquímica , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Insuficiencia Renal Crónica/complicaciones , Factores de RiesgoRESUMEN
Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of ß-amyloid (Aß) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aß levels and amyloid plaque deposition by promoting the recruitment and Aß phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1ß, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , Interleucina-33/administración & dosificación , Enfermedad de Alzheimer/diagnóstico , Animales , Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/diagnóstico , Citocinas/metabolismo , Femenino , Masculino , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/administración & dosificación , Resultado del TratamientoRESUMEN
Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-ß oligomers (Aß), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Receptor EphA4/metabolismo , Sinapsis/fisiología , Enfermedad de Alzheimer/metabolismo , Animales , Hipocampo/metabolismo , Ratones , Ratones Transgénicos , Receptor EphA4/genética , Sinapsis/metabolismoRESUMEN
The proper growth and arborization of dendrites in response to sensory experience are essential for neural connectivity and information processing in the brain. Although neuronal activity is important for sculpting dendrite morphology, the underlying molecular mechanisms are not well understood. Here, we report that cyclin-dependent kinase 5 (Cdk5)-mediated transcriptional regulation is a key mechanism that controls activity-dependent dendrite development in cultured rat neurons. During membrane depolarization, Cdk5 accumulates in the nucleus to regulate the expression of a subset of genes, including that of the neurotrophin brain-derived neurotrophic factor, for subsequent dendritic growth. Furthermore, Cdk5 function is mediated through the phosphorylation of methyl-CpG-binding protein 2, a key transcriptional repressor that is mutated in the mental disorder Rett syndrome. These findings collectively suggest that the nuclear import of Cdk5 is crucial for activity-dependent dendrite development by regulating neuronal gene transcription during neural development. SIGNIFICANCE STATEMENT: Neural activity directs dendrite development through the regulation of gene transcription. However, how molecular signals link extracellular stimuli to the transcriptional program in the nucleus remains unclear. Here, we demonstrate that neuronal activity stimulates the translocation of the kinase Cdk5 from the cytoplasmic compartment into the nucleus; furthermore, the nuclear localization of Cdk5 is required for dendrite development in cultured neurons. Genome-wide transcriptome analysis shows that Cdk5 deficiency specifically disrupts activity-dependent gene transcription of bdnf. The action of Cdk5 is mediated through the modulation of the transcriptional repressor methyl-CpG-binding protein 2. Therefore, this study elucidates the role of nuclear Cdk5 in the regulation of activity-dependent gene transcription and dendritic growth.
Asunto(s)
Quinasa 5 Dependiente de la Ciclina/fisiología , Dendritas/metabolismo , Regulación del Desarrollo de la Expresión Génica , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo , Animales , Células Cultivadas , Dendritas/genética , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Transgénicos , RatasRESUMEN
The radial migration of newborn neurons is critical for the lamination of the cerebral cortex. Proper neuronal migration requires precise and rapid reorganization of the actin and microtubule cytoskeleton. However, the underlying signaling mechanisms controlling cytoskeletal reorganization are not well understood. Here, we show that Mst3, a serine/threonine kinase highly expressed in the developing mouse brain, is essential for radial neuronal migration and final neuronal positioning in the developing mouse neocortex. Mst3 silencing by in utero electroporation perturbed the multipolar-to-bipolar transition of migrating neurons and significantly retards radial migration. Although the kinase activity of Mst3 is essential for its functions in neuronal morphogenesis and migration, it is regulated via its phosphorylation at Ser79 by a serine/threonine kinase, cyclin-dependent kinase 5 (Cdk5). Our results show that Mst3 regulates neuronal migration through modulating the activity of RhoA, a Rho-GTPase critical for actin cytoskeletal reorganization. Mst3 phosphorylates RhoA at Ser26, thereby negatively regulating the GTPase activity of RhoA. Importantly, RhoA knockdown successfully rescues neuronal migration defect in Mst3-knockdown cortices. Our findings collectively suggest that Cdk5-Mst3 signaling regulates neuronal migration via RhoA-dependent actin dynamics.
Asunto(s)
Movimiento Celular/fisiología , Quinasa 5 Dependiente de la Ciclina/fisiología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Unión al GTP rho/antagonistas & inhibidores , Proteínas de Unión al GTP rho/fisiología , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Células Cultivadas , Activación Enzimática/fisiología , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Datos de Secuencia Molecular , Neocórtex/metabolismo , Proteínas del Tejido Nervioso/fisiología , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Ratas , Proteína de Unión al GTP rhoARESUMEN
The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, how the receptor-associated actin is coordinately regulated is not fully understood. We report here that Coronin 6, a newly identified member of the coronin family, is highly enriched at adult NMJs and regulates AChR clustering through modulating the interaction between receptors and the actin cytoskeletal network. Experiments with cultured myotubes reveal that Coronin 6 is important for both agrin- and laminin-induced AChR clustering. Furthermore, Coronin 6 forms a complex with AChRs and actin in a manner dependent on its C-terminal region and a conserved Arg(29) residue at the N terminus, both of which are critical for the cytoskeletal anchorage of AChRs. Importantly, in vivo knockdown of Coronin 6 in mouse skeletal muscle fibers leads to destabilization of AChR clusters. Together, these findings demonstrate that Coronin 6 is a critical regulator of AChR clustering at the postsynaptic region of the NMJs through modulating the receptor-anchored actin cytoskeleton.