Neurotrophins regulate ApoER2 proteolysis through activation of the Trk signaling pathway.

BACKGROUND: ApoER2 and the neurotrophin receptors Trk and p75(NTR) are expressed in the CNS and regulate key functional aspects of neurons, including development, survival, and neuronal function. It is known that both ApoER2 and p75(NTR) are processed by metalloproteinases, followed by regulated intramembrane proteolysis. TrkA activation by nerve growth factor (NGF) increases the proteolytic processing of p75(NTR) mediated by ADAM17. Reelin induces the sheeding of ApoER2 ectodomain depending on metalloproteinase activity. However, it is not known if there is a common regulation mechanism for processing these receptors. RESULTS: We found that TrkA activation by NGF in PC12 cells induced ApoER2 processing, which was dependent on TrkA activation and metalloproteinases. NGF-induced ApoER2 proteolysis was independent of mitogen activated protein kinase activity and of phosphatidylinositol-3 kinase activity. In contrast, the basal proteolysis of ApoER2 increased when both kinases were pharmacologically inhibited. The ApoER2 ligand reelin regulated the proteolytic processing of its own receptor but not of p75(NTR). Finally, in primary cortical neurons, which express both ApoER2 and TrkB, we found that the proteolysis of ApoER2 was also regulated by brain-derived growth factor (BDNF). CONCLUSIONS: Our results highlight a novel relationship between neurotrophins and the reelin-ApoER2 system, suggesting that these two pathways might be linked to regulate brain development, neuronal survival, and some pathological conditions.

Sorting nexin 17 regulates ApoER2 recycling and reelin signaling.

ApoER2 is a member of the low density-lipoprotein receptor (LDL-R) family. As a receptor for reelin, ApoER2 participates in neuronal migration during development as well as synaptic plasticity and survival in the adult brain. A previous yeast two-hybrid screen showed that ApoER2 is a binding partner of sorting nexin 17 (SNX17) - a cytosolic adaptor protein that regulates the trafficking of several membrane proteins in the endosomal pathway, including LRP1, P-selectin and integrins. However, no further studies have been performed to investigate the role of SNX17 in ApoER2 trafficking and function. In this study, we present evidence based on GST pull-down and inmunoprecipitation assays that the cytoplasmic NPxY endocytosis motif of ApoER2 interacts with the FERM domain of SNX17. SNX17 stimulates ApoER2 recycling in different cell lines including neurons without affecting its endocytic rate and also facilitates the transport of ApoER2 from the early endosomes to the recycling endosomes. The reduction of SNX17 was associated with accumulation of an ApoER2 carboxy-terminal fragment (CTF). In addition, in SNX17 knockdown cells, constitutive ApoER2 degradation was not modified, whereas reelin-induced ApoER2 degradation was increased, implying that SNX17 is a regulator of the receptor's half-life. Finally, in SNX17 silenced hippocampal and cortical neurons, we underscored a positive role of this endosomal protein in the development of the dendritic tree and reelin signaling. Overall, these results establish the role of SNX17 in ApoER2 trafficking and function and aid in identifying new links between endocytic trafficking and receptor signaling.

Mechanisms regulating hepatic SR-BI expression and their impact on HDL metabolism.

High-density lipoproteins (HDLs) are major carriers of cholesterol in the bloodstream and are critical in regulating cholesterol homeostasis in vivo. The first molecularly well-defined and physiologically relevant HDL receptor to be characterized was the scavenger receptor class B type I (SR-BI), a cell surface glycoprotein most highly expressed in liver and steroidogenic tissues. The HDL receptor SR-BI plays a key role in mediating selective HDL cholesterol (HDL-C) uptake in the liver, thus controlling cholesterol levels in plasma and the transhepatic traffic of this lipid into bile. SR-BI knockout mice exhibit increased plasma HDL-C levels and abnormally large HDL particles as well as reduced biliary cholesterol levels. Conversely, transgenic mice overexpressing SR-BI in the liver have markedly reduced plasma HDL levels, accelerated HDL-C clearance, increased hepatic selective cholesterol uptake, and raised biliary cholesterol content. The regulation of HDL-C metabolism by hepatic SR-BI is relevant for cardiovascular health as shown in mouse models where the lack of this receptor in the liver induces atherosclerotic lesions, whereas hepatic SR-BI overexpression entails a reduction of atherosclerosis. This review summarizes some recent progress in understanding the mechanisms that regulate hepatic SR-BI expression at transcriptional and post-transcriptional levels, providing opportunities for novel approaches that may improve HDL-dependent cholesterol homeostasis and lead to better prevention and treatment of atherosclerosis in humans.

[Molecular epidemiology of tuberculosis in Almeria (Spain). Factors associated with recent transmission]. / Epidemiología molecular de la tuberculosis en Almería. Factores asociados a transmisión reciente.

BACKGROUND: Molecular epidemiology is used in tuberculosis (TB) to identify clusters in which the cases are assumed to belong to the same recent transmission chain. An endogenous reactivation of latent TB is considered when the Mycobacterium tuberculosis isolates have a unique genotype. OBJECTIVE: To describe factors associated with recent transmission of TB in Almeria, from 2003-2007. METHODS: We conducted an observational prospective study that included patients with Mycobacterium tuberculosis positive culture. The strains were genotyped by Restriction Fragment Length Polymorphism and spoligotyping. Adjusted odds ratio and 95% confidence intervals were calculated to study factors associated with cluster groups, using a multivariate logistic regression model. RESULTS: We analysed 427 isolates, of which 71% were from males and 56.2% of them belonged to foreign residents. Furthermore, 44% were classified as a cluster. The resistance to isoniazid was 8.4%. The factors associated with clusters were age, principally the group under 10 years (adjusted OR=12.75; 95% CI, 2.52-64.58) and the group aged between 50-59 years (adjusted OR=13.85; 95% CI, 3.04-63.17), and born in Spain (adjusted OR=2.17; 95% CI, 1.41-3.36). CONCLUSIONS: In Almeria, native population, children under 10 years old and patients aged between 50-59 years have more probability to belong to the same recent transmission chain. The molecular epidemiology can be used to find out which population groups need more control and this information must be used in tuberculosis prevention programs.

Epidemiología molecular de la tuberculosis en Almería. Factores asociados a transmisión reciente / Molecular epidemiology of tuberculosis in Almeria (Spain). Factors associated with recent transmission

Introducción La epidemiología molecular aplicada a la tuberculosis (TB) permite identificar clusters, cuyos miembros se asume que pertenecen a la misma cadena de transmisión reciente. Se considera reactivación endógena cuando el aislado presenta un genotipo único. Objetivo describir los factores asociados a la transmisión reciente de la TB en Almería, en el período 2003-2007. Métodos Se realizó un estudio observacional prospectivo de pacientes con tuberculosis, cuyos aislados fueron caracterizados genotípicamente mediante Restriction Fragment Length Polymorphism y spoligotyping. Se calcularon odds ratio y sus intervalos de confianza del 95% y mediante regresión logística se analizaron los factores asociados a pertenecer a un cluster. Resultados Se analizaron 427 aislados, de los cuales el 71% procedía de varones y 56,2% de ellos pertenecían a extranjeros. Un 44% de los pacientes participaba en algún cluster. La resistencia a isoniazida fue del 8,4%. Los factores relacionados con cluster fueron la edad, fundamentalmente los menores de 10 años (OR ajustada=12,75; IC del 95%, 2,52-64,58) y el grupo entre 50 y 59 años (OR ajustada=13,85; IC del 95%, 3,04-63,17), así como los nacidos en España (OR ajustada=2,17; IC del 95%, 1,41-3,36).Conclusiones En Almería, los autóctonos presentan más posibilidades de estar implicados en una cadena de transmisión reciente, así como los pacientes de ciertos tramos de edad como los niños menores de 10 años, y los de 50-59 años. La epidemiología molecular permite conocer qué grupos de población requieren mayor control, y reorientar hacia ellos los programas de prevención de la tuberculosis (AU)

Background: Molecular epidemiology is used in tuberculosis (TB) to identify clusters in which the cases are assumed to belong to the same recent transmission chain. An endogenous reactivation of latent TB is considered when the Mycobacterium tuberculosis isolates have a unique genotype. Objective: To describe factors associated with recent transmission of TB in Almeria, from 2003-2007.Methods: We conducted an observational prospective study that included patients with Mycobacterium tuberculosis positive culture. The strains were genotyped by Restriction Fragment Length Polymorphismand spoligotyping. Adjusted odds ratio and 95% confidence intervals were calculated to study factors associated with cluster groups, using a multivariate logistic regression model. Results: We analysed 427 isolates, of which 71% were from males and 56.2% of them belonged to foreign residents. Furthermore, 44% were classified as a cluster. The resistance to isoniazid was 8.4%. The factors associated with clusters were age, principally the group under 10 years (adjusted OR= 12.75; 95% CI, 2.52-64.58) and the group aged between 50-59 years (adjusted OR= 13.85; 95% CI, 3.04-63.17), and born in Spain (adjusted OR= 2.17; 95% CI, 1.41-3.36).Conclusions: In Almeria, native population, children under 10 years old and patients aged between 50-59years have more probability to belong to the same recent transmission chain. The molecular epidemiology can be used to find out which population groups need more control and this information must be used intuberculosis prevention programs (AU)

Afectación de las redes neurales atencionales durante el envejecimiento saludable / Attentional neural networks impairment in healthy aging

Introducción. Existen diversas evidencias de que el proceso de envejecimiento natural ocasiona un declive en las diferentes funciones cognitivas, incluyendo la atención. Sujetos y métodos. Dos grupos de estudio: jóvenes (32,5 ± 9,7 años) y adultos mayores saludables (62,7 ± 4,7 años). Como instrumento para evaluar la atención utilizamos el test de redes atencionales –Attention Network Test (ANT)–. Resultados. En el ANT, en lo que respecta al tiempo de reacción ante las diferentes condiciones que se dan (sin clave, clave central, clave espacial, congruencia e incongruencia), encontramos diferencias significativas en todas ellas entre ambos grupos (p < 0,001). En cuanto al análisis de redes, éstas no mostraron diferencias entre ambas muestras. Si comparamos el efecto por bloques del ANT, el análisis post hoc mostró que la red de orientación para los sujetos jóvenes presenta un beneficio por el uso de las claves espaciales en el primer bloque, mientras que para los sexagenarios no. Además, la red de alerta mostró un mayor efecto en el primer bloque respecto del segundo en los adultos mayores y el efecto opuesto para la red ejecutiva y de orientación. Conclusiones. Los datos obtenidos muestran que existe una disminución en la velocidad de procesamiento en las personas mayores. En el caso particular de la red de orientación parece que los mayores requieren un intervalo temporal mayor para emplear las claves espaciales, aunque posteriormente tras cierto entrenamiento pueden beneficiarse de éstas casi al mismo nivel que los sujetos jóvenes (AU)

Introduction. Diverse evidences have shown that the process of natural aging causes a decline in different cognitive functions, including among them the attentional process. Aim. To determine how the healthy aging affects to the different attentional networks. Subjects and methods. Two groups: young subjects (32.5 ± 9.7 years) and an elderly group (62.7 ± 4.7 years). As instrument to evaluate the attention process the ANT (Attention Network Test) was used. Results. Highly significant differences were observed for all conditions involved in the ANT (no cue, center cue, spatial cue, congruent and incongruent) between both groups (p < 0.001). As for the analysis of network effects, no one showed differences between the two groups. Considering the block variable, the post hoc analysis showed that the orienting network for the young subjects exhibited a normal benefit in the first block while the elderly group don’t show that benefit caused by the deficiency using spatial cues. Moreover, the alerting network showed a bigger effect in the first block regarding the second one in the older adults and the opposed effect for the executive and orienting network was observed. Conclusions. The obtained data show that a decrease exists in the speed processing in the elderly group. In the orienting network seems that the older adults require a bigger training period to use the spatial cues, although later on, they can benefit from the same cues almost at the same level that the young subjects (AU)