Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer.

The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer's disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/-)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/-) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aß) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/-) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aß in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aß pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.

Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer's disease.

Synaptic bioenergetic deficiencies may be associated with early Alzheimer's disease (AD). To explore this concept, we assessed pre-synaptic mitochondrial function in hemizygous (+/-)TgMcGill-R-Thy1-APP rats. The low burden of Aß and the wide array of behavioral and cognitive impairments described in 6-month-old hemizygous TgMcGill-R-Thy1-APP rats (Tg(+/-)) support their use to investigate synaptic bioenergetics deficiencies described in subjects with early Alzheimer's disease (AD). In this report, we show that pre-synaptic mitochondria from Tg(+/-) rats evidence a decreased respiratory control ratio and spare respiratory capacity associated with deficits in complex I enzymatic activity. Cognitive impairments were prevented and bioenergetic deficits partially reversed when Tg(+/-) rats were fed a nutritionally complete diet from weaning to 6-month-old supplemented with pyrroloquinoline quinone, a mitochondrial biogenesis stimulator with antioxidant and neuroprotective effects. These results provide evidence that, as described in AD brain and not proven in Tg mice models with AD-like phenotype, the mitochondrial bioenergetic capacity of synaptosomes is not conserved in the Tg(+/-) rats. This animal model may be suitable for understanding the basic biochemical mechanisms involved in early AD.

The effect of maternal near miss on adverse infant nutritional outcomes.

OBJECTIVES:: To evaluate the association between self-reported maternal near miss and adverse nutritional status in children under one year of age. METHODS:: This study is a secondary analysis of a study in which women who took their children under one year of age to the national vaccine campaign were interviewed. The self-reported condition of maternal near miss used the criteria of Intensive Care Unit admission; eclampsia; blood transfusion and hysterectomy; and their potential associations with any type of nutritional disorder in children, including deficits in weight-for-age, deficits in height-for-age, obesity and breastfeeding. The rates of near miss for the country, regions and states were initially estimated. The relative risks of infant adverse nutritional status according to near miss and maternal/childbirth characteristics were estimated with their 95% CIs using bivariate and multiple analyses. RESULTS:: The overall prevalence of near miss was 2.9% and was slightly higher for the Legal Amazon than for other regions. No significant associations were found with nutritional disorders in children. Only a 12% decrease in overall maternal breastfeeding was associated with near miss. Living in the countryside and child over 6 months of age increased the risk of altered nutritional status by approximately 15%, while female child gender decreased this risk by 30%. Maternal near miss was not associated with an increased risk of any alteration in infant nutritional status. CONCLUSIONS:: There was no association between maternal near miss and altered nutritional status in children up to one year of age. The risk of infant adverse nutritional status was greater in women living in the countryside, for children over 6 months of age and for male gender.

The effect of maternal near miss on adverse infant nutritional outcomes

OBJECTIVES: To evaluate the association between self-reported maternal near miss and adverse nutritional status in children under one year of age. METHODS: This study is a secondary analysis of a study in which women who took their children under one year of age to the national vaccine campaign were interviewed. The self-reported condition of maternal near miss used the criteria of Intensive Care Unit admission; eclampsia; blood transfusion and hysterectomy; and their potential associations with any type of nutritional disorder in children, including deficits in weight-for-age, deficits in height-for-age, obesity and breastfeeding. The rates of near miss for the country, regions and states were initially estimated. The relative risks of infant adverse nutritional status according to near miss and maternal/childbirth characteristics were estimated with their 95% CIs using bivariate and multiple analyses. RESULTS: The overall prevalence of near miss was 2.9% and was slightly higher for the Legal Amazon than for other regions. No significant associations were found with nutritional disorders in children. Only a 12% decrease in overall maternal breastfeeding was associated with near miss. Living in the countryside and child over 6 months of age increased the risk of altered nutritional status by approximately 15%, while female child gender decreased this risk by 30%. Maternal near miss was not associated with an increased risk of any alteration in infant nutritional status. CONCLUSIONS: There was no association between maternal near miss and altered nutritional status in children up to one year of age. The risk of infant adverse nutritional status was greater in women living in the countryside, for children over 6 months of age and for male gender.

Consentimiento Informado para Biobancos: Un debate ético abierto / Informed Consent for Biobanks: An open ethical debate

Los Biobancos con fines de Investigación están aumentando en número e importancia, con un gran potencial que contribuye a la generación de conocimiento pertinente para la solución de problemas en salud. El reclutamiento de donantes es vital para su éxito. Sin embargo, este proceso tiene implicaciones importantes de carácter ético, legal y social. El consentimiento informado requerido para la participación del donante impone desafíos éticos importantes en torno a la privacidad, confidencialidad, uso secundario de muestras y datos para estudios futuros, retorno de resultados, intercambio de datos, distribución de beneficios entre otras. Diferentes modelos de consentimiento informado han sido propuestos para responder a algunos de estos retos éticos . Sin embargo, no se ha llegado a un acuerdo, por lo tanto la discusión continúa abierta. Este trabajo pretende contribuir con la discusión, considerando fundamental el significado y el valor del proceso de consentimiento informado para la participación en investigación biomédica. Se discuten los diferentes tipos de consentimiento que se están utilizando actualmente evaluando el nivel de control y autodeterminación por parte del donante.

Biobanks with Research purposes are increasing in number and importance, with great potential that contributes to the generation of knowledge relevant to solving health problems. For the Biobanks to be successful, donor recruitment is essential. However, this process has important ethical, legal and social implications. Informed consent required for the participation of the donor imposes significant ethical challenges about privacy, confidentiality, secondary use of samples and data for future studies, return of results, data exchange, and distribution of the benefits among others. Different templates of informed consent have been proposed to address some of these ethical challenges. However, an agreement has not been reached, and the discussion remains open. This work aims to contribute to the discussion, considering the meaning and value of the informed consent process for participation in biomedical research, and examines the different types of consents currently used evaluating the level of control and self-determination displayed by the donor.

Biobanco Herramienta fundamental para la investigación biomédica actual / Biobank Fundamental tool for today's biomedical research

La investigación biomédica enfocada a la preservación de la salud y manejo de la enfermedad requiere hoy del trabajo articulado bidireccional entre básicos y clínicos, lo cual ha generado una nueva tendencia, denominada investigación traslacional. Este tipo de investigación se fundamenta en poder brindar una atención en salud oportuna, pertinente, eficaz y personalizada, para lo cual se requieren muestras biológicas e información clínica asociada, garantizando a su vez seguridad, calidad y confidencialidad para los donantes. Promover la investigación traslacional y la aplicación de los avances del conocimiento y de la tecnología derivados de la investigación y la innovación, requiere del apoyo de infraestructuras de fácil acceso que faciliten la rápida demostración experimental de una hipótesis o la comprobación de un modelo simulado previamente. Dentro de las diversas plataformas biomédicas y de salud existentes, los Biobancos, en sus diferentes modalidades, se constituyen en una de las más atractivas plataformas a la hora de contribuir a establecer puentes entre la investigación básica y clínica, con la práctica asistencial. La necesidad de contar con muestras biológicas humanas de alta calidad y, al mismo tiempo, la obligación de preservar los derechos de los donantes, ha elevado la gestión de los Biobancos a la categoría de disciplina científico-técnica, con una complejidad particular que involucra múltiples aspectos entre los cuales se incluyen aspectos científicos, técnicos, éticos, jurídicos y sociales. Esta serie de artículos, que serán publicados en los diferentes números de la revista durante el 2016, tienen como objetivo hacer una revisión crítica de los aspectos más relevantes en torno a la gestión de los Biobancos con fines de investigación y proponer una serie de guías de manejo del material biológico humano a conservar las cuales se han desarrollado en el marco del Programa Cardiecol.

Biomedical research aimed at the preservation of health and disease management requires nowadays a bidirectional and articulated collaboration between basic and clinical work, which has generated a new trend called translational research. This type of research is based on the ability to provide timely, relevant, effective and personalized healthcare, for which biological samples, and associated clinical information are required, while ensuring safety, quality and confidentiality for donors. In order to promote translational research and the application of the advances in knowledge and technology from research and innovation, the support of accessible infrastructure is required to facilitate the rapid experimental demonstration of an hypothesis or testing a previously simulated model. Among the diverse biomedical and healthcare existing platforms, the Biobanks, in their various forms constitute one of the most attractive platforms contributing to establish bridges between the basic and clinical research with the clinical practice. The need for human biological samples of high quality, and at the same time, the obligation to preserve the rights of donors, has raised the Biobanks' management to the scientific and technical category, with the added particular complexity of involving multiple aspects including scientific, ethical, legal, and social factors. This series of articles that will be published in different issues of the magazine in 2016, aims to make a critical review of the most relevant aspects regarding the management of Biobanks for research, and to propose a series of guidelines for the management of human biological material as developed by the program Cardiecol.

Maternal near miss among women using the public health system in the Amazon and Northeast regions of Brazil.

OBJECTIVE: To assess the prevalence of pregnancy complications identified as maternal near miss (MNM) and associated factors among women using the public health care system in the Amazon and Northeast regions of Brazil. METHODS: A secondary analysis of a population-based survey conducted in 2010 was performed focusing on women self-reporting maternal complications. The main outcome was MNM, pragmatically defined as intensive care unit admission, eclampsia, hysterectomy, or blood transfusion. In addition, the risk of MNM was estimated for certain sociodemographics and characteristics of care received. Poisson regression was performed, generating adjusted prevalence ratios (PRadj) with 95% confidence intervals (95%CI). RESULTS: A total of 13 044 women (77%) who had given birth during the prior year using the public health system were interviewed. At least one complication was reported by 37.5%, with hemorrhage (28.4%) and infection (8.3%) being the most frequent. The overall MNM ratio was 31.5 per 1 000 live births, higher for the Amazon region than for the Northeast. Factors with a higher risk for developing MNM were: indigenous ethnicity (PRadj 2.77; 95% CI: 1.50-5.14), more than one hour to reach the hospital (PRadj 1.55; 95%CI: 1.06-2.25), being refused by a full hospital and having to find another one (PRadj 1.49; 95%CI: 1.03-2.16), cesarean section (PRadj 2.56; 95%CI: 1.90-3.44), and public prenatal care (PRadj 1.95; 95%CI: 1.06-3.61). CONCLUSIONS: Users of public health system in the Amazon and Northeast regions of Brazil have high MNM rates. Some characteristics of the women and of the care they received represent inequalities associated with higher risk for MNM. Specific actions are required to improve maternal health programs in these expansive areas of the country.

Maternal near miss among women using the public health system in the Amazon and Northeast regions of Brazil / Morbilidad materna extremadamente grave entre las usuarias del sistema de salud pública en las regiones amazónica y noreste del Brasil

OBJECTIVE: To assess the prevalence of pregnancy complications identified as maternal near miss (MNM) and associated factors among women using the public health care system in the Amazon and Northeast regions of Brazil. METHODS: A secondary analysis of a population-based survey conducted in 2010 was performed focusing on women self-reporting maternal complications. The main outcome was MNM, pragmatically defined as intensive care unit admission, eclampsia, hysterectomy, or blood transfusion. In addition, the risk of MNM was estimated for certain sociodemographics and characteristics of care received. Poisson regression was performed, generating adjusted prevalence ratios (PRadj) with 95% confidence intervals (95%CI). RESULTS: A total of 13 044 women (77%) who had given birth during the prior year using the public health system were interviewed. At least one complication was reported by 37.5%, with hemorrhage (28.4%) and infection (8.3%) being the most frequent. The overall MNM ratio was 31.5 per 1 000 live births, higher for the Amazon region than for the Northeast. Factors with a higher risk for developing MNM were: indigenous ethnicity (PRadj 2.77; 95% CI: 1.50-5.14), more than one hour to reach the hospital (PRadj 1.55; 95%CI: 1.06-2.25), being refused by a full hospital and having to find another one (PRadj 1.49; 95%CI: 1.03-2.16), cesarean section (PRadj 2.56; 95%CI: 1.90-3.44), and public prenatal care (PRadj 1.95; 95%CI: 1.06-3.61). CONCLUSIONS: Users of public health system in the Amazon and Northeast regions of Brazil have high MNM rates. Some characteristics of the women and of the care they received represent inequalities associated with higher risk for MNM. Specific actions are required to improve maternal health programs in these expansive areas of the country.

OBJETIVO: Evaluar la prevalencia de las complicaciones del embarazo establecidas como morbilidad materna extremadamente grave (MMEG), y los factores asociados, entre las usuarias del sistema de atención de salud pública en las zonas amazónica y noreste del Brasil. MÉTODOS:Se realizó un análisis secundario de una encuesta poblacional llevada a cabo en el 2010 y centrado en las mujeres que autonotificaban complicaciones obstétricas. El principal resultado fue la MMEG, definida a efectos prácticos como ingreso en una unidad de cuidados intensivos, eclampsia, histerectomía o transfusión de sangre. Se calculó además el riesgo de MMEG para determinadas características sociodemográficas y de la atención recibida. Se llevó a cabo una regresión de Poisson y se generaron las razones de prevalencia ajustadas (RPa) con intervalos de confianza de 95% (IC 95%). RESULTADOS:Se entrevistó a un total de 13 044 mujeres (77%) que habían dado a luz durante el año previo en el sistema de salud pública. Un 37,5% notificó como mínimo una complicación; la hemorragia (28,4%) y la infección (8,3%) fueron las más frecuentes. El índice general de MMEG fue de 31,5 por 1 000 nacidos vivos, más elevado en la región amazónica que en la noreste. Los factores que comportaron un riesgo mayor de MMEG fueron la etnicidad autóctona (RPa 2,77; IC 95% = 1,50-5,14), precisar más de una hora para llegar al hospital (RPa 1,55; IC 95% = 1,06-2,25), no ser admitida en un hospital por estar completo y tener que encontrar otro (RPa 1,49; IC 95% = 1,03-2,16), la cesárea (RPa 2,56; IC 95% = 1,90-3,44), y la asistencia prenatal pública (RPa 1,95; IC 95% = 1,06-3,61). CONCLUSIONES: Las usuarias del sistema de salud pública en las regiones amazónica y noreste del Brasil muestran tasas elevadas de morbilidad materna extremadamente grave. Algunas características de las mujeres y de la atención recibida comportan desigualdades asociadas con un riesgo mayor de morbilidad materna extremadamente grave. Se requieren acciones específicas que mejoren los programas de salud materna en estas amplias zonas del país.

Interleukin-1ß and tumor necrosis factor-α: reliable targets for protective therapies in Parkinson's Disease?

Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson's Disease (PD). Two prototypic pro-inflammatory cytokines interleukin-1ß (IL-1) and tumor necrosis factor-α (TNF) have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g., their expression is not induced by each other) and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN). In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF-α clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1ß or TNF-α expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective) effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti-IL-1ß or TNF-α therapies against PD.

Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid ß (Aß) peptide catabolism and functionality.

Studies of post-mortem brains from Alzheimer disease patients suggest that oxidative damage induced by mitochondrial amyloid ß (mitAß) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitAß metabolism is unknown. One of the proteases involved in mitAß catabolism is the long insulin-degrading enzyme (IDE) isoform (IDE-Met(1)). However, the mechanisms of its expression are unknown, and its presence in brain is uncertain. We detected IDE-Met(1) in brain and showed that its expression is regulated by the mitochondrial biogenesis pathway (PGC-1α/NRF-1). A strong positive correlation between PGC-1α or NRF-1 and long IDE isoform transcripts was found in non-demented brains. This correlation was weaker in Alzheimer disease. In vitro inhibition of IDE increased mitAß and impaired mitochondrial respiration. These changes were restored by inhibition of γ-secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met(1) links the mitochondrial biogenesis pathway with mitAß levels and organelle functionality.

Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aß metabolism.

Cerebral amyloid ß (Aß) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in Aß generation while insulin-degrading enzyme (IDE) partakes in Aß proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aß accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at -379/-372 and -310-303 from the first translation start site in the -575/-19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aß metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD.

Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease.

The accumulation of amyloid-beta (Abeta) peptides in senile plaques is one of the hallmarks of Alzheimer's disease (AD) progression. The endocytic pathway has been proposed as a major subcellular site for Abeta generation while the compartments in which Abeta-degrading proteases interact with Abeta are still elusive. It was suggested that extracellular Abeta degradation may take place by plasma-membrane associated proteases or by extracellular proteases, among which insulin-degrading enzyme (IDE) is the most relevant. However, the mechanisms of IDE secretion are poorly understood. In the present study we used N2a cells to explore if IDE is indeed released through exosomes and the effect of exosomes release on extracellular levels of Abeta. We demonstrated that proteolytically-active plasma membrane associated-IDE is routed in living N2a cells to multivesicular bodies and subsequently, a major fraction is sorted to exosomes. We described that extracellular IDE levels decrease if the generation of multivesicular bodies is interfered and may be positively modulated by exosomes release under stress-induced conditions. Our results reinforce the relevance of functional IDE in the catabolism of extracellular Abeta.

Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Abeta and insulin degradation.

BACKGROUND: Insulin degrading enzyme (IDE) is implicated in the regulation of amyloid beta (Abeta) steady-state levels in the brain, and its deficient expression and/or activity may be a risk factor in sporadic Alzheimer's disease (AD). Although IDE sub-cellular localization has been well studied, the compartments relevant to Abeta degradation remain to be determined. RESULTS: Our results of live immunofluorescence, immuno gold electron-microscopy and gradient fractionation concurred to the demonstration that endogenous IDE from brain tissues and cell cultures is, in addition to its other localizations, a detergent-resistant membrane (DRM)-associated metallopeptidase. Our pulse chase experiments were in accordance with the existence of two pools of IDE: the cytosolic one with a longer half-life and the membrane-IDE with a faster turn-over. DRMs-associated IDE co-localized with Abeta and its distribution (DRMs vs. non-DRMs) and activity was sensitive to manipulation of lipid composition in vitro and in vivo. When IDE was mis-located from DRMs by treating cells with methyl-beta-cyclodextrin (MbetaCD), endogenous Abeta accumulated in the extracellular space and exogenous Abeta proteolysis was impaired. We detected a reduced amount of IDE in DRMs of membranes isolated from mice brain with endogenous reduced levels of cholesterol (Chol) due to targeted deletion of one seladin-1 allele. We confirmed that a moderate shift of IDE from DRMs induced a substantial decrement on IDE-mediated insulin and Abeta degradation in vitro. CONCLUSION: Our results support the notion that optimal substrate degradation by IDE may require its association with organized-DRMs. Alternatively, DRMs but not other plasma membrane regions, may act as platforms where Abeta accumulates, due to its hydrophobic properties, reaching local concentration close to its Km for IDE facilitating its clearance. Structural integrity of DRMs may also be required to tightly retain insulin receptor and IDE for insulin proteolysis. The concept that mis-location of Abeta degrading proteases away from DRMs may impair the physiological turn-over of Abeta in vivo deserves further investigation in light of therapeutic strategies based on enhancing Abeta proteolysis in which DRM protease-targeting may need to be taken into account.

Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic tg2576 mice with Alzheimer pathology.

It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid beta (Abeta) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Abeta precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Abeta and massive Abeta deposition into plaques. At this stage, IDE appeared surrounding Abeta fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Abeta-mediated inflammation process. When primary astrocytes were exposed to fibrillar Abeta in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Abeta-triggered inflammation.