Amyloid Peptide Induced Neuroinflammation Increases the P2X7 Receptor Expression in Microglial Cells, Impacting on Its Functionality

Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), is essential to neuroinflammation and neurotoxicity induced by Aβ. P2X7R is upregulated on microglial cells around the senile plaques. This upregulation progressively rises with age and is parallel with an accumulation of senile plaques and also correlates with the synaptic toxicity detected both in animal models reproducing AD and human patients of AD. Furthermore, the late onset of the first AD-associated symptoms suggests that aging associated-changes may be relevant to the disease progression. Thus, microglia motility and its capacity to respond to exogenous ATP stimulus decrease with aging. To evaluate whether the P2X7R age related-changes on microglia cells may be relevant to the AD progression, we generated a new transgenic mouse model crossing an Aβ peptide mouse model, J20 mice and the P2X7R reporter mice P2X7REGFP. Our results indicate that neuroinflammation induced by Aβ peptide causes changes in the P2X7R distribution pattern, increasing it s expression in microglial cells at advanced and late stages, when microgliosis occurs, but not in the early stages, in the absence of microgliosis. In addition, we found that P2X7R activation promotes microglial cells migration to senile plaques but decreases their phagocytic capacity. Moreover, we found a significant reduction of P2X7R transcription on neuronal cells at the early and advanced stages, but not at the late stages. Since previous studies have reported that either pharmacological inhibition or selective downregulation of P2X7R significantly improve behavioral alterations and reduce the incidence and size of senile plaques in the early and advanced stages of AD, the results presented here provide new evidence, indicating that this therapeutic approach could be also efficient in the late stages of the disease

The urban impact of COVID-19: six neighbourhoods, three cities and three countries in social network data

La situación de emergencia sanitaria COVID-19 ha impactado múltiples dimensiones de la compleja estructura física, social, funcional y económica de las ciudades. Esta investigación lleva a cabo un diagnóstico comparado sobre algunos cambios y transformaciones que se han producido en el entorno urbano a causa de la crisis y que se reflejan en los datos de redes sociales geolocalizadas. Para ello, los datos de Google Places y Twitter se adoptan como principal fuente de información. Se propone un método mixto, cualitativo y cuantitativo, para analizar el aumento y la pérdida de actividad económica (Google Places) y presencia humana (Twitter) en dos periodos, pre y pos-pandemia. Como caso de estudio, se analizan dos ámbitos con condiciones socioeconómicas muy diferenciadas en tres ciudades localizadas en países que han adoptado distintas medidas de contención de la pandemia –Valencia en España; Ciudad de México en México y Gotemburgo en Suecia–. El diagnóstico informado por estas redes sociales es de gran utilidad para formular estrategias útiles tanto para identificar los cambios que se han venido produciendo como para afrontar futuros escenarios disruptivos.The COVID-19 health emergency has impacted multiple dimensions of the complex physical, social, functional and economic structure of cities. This research encompasses a comparative diagnosis of some of the changes and transformations that have occurred in the urban environment due to the crisis and are reflected in geolocalised social network data. For this purpose, data from Google Places and Twitter are adopted as the main source of information. A mixed qualitative and quantitative methodology is proposed to analyse the increase and loss of economic activity (Google Places) and human presence (Twitter) in two periods: pre- and post-pandemic. As a case study, two areas with very different socio-economic conditions are analysed in three cities located in countries that adopted different pandemic restrictions measures - Valencia in Spain, Mexico City in Mexico and Gothenburg in Sweden. The diagnosis reported by these social networks is of great use in formulating useful strategies both for identifying the changes that have been taking place and for dealing with future disruptive scenarios.Esta investigación ha sido cofinanciada por la Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital. Generalitat Valenciana, España (GV/2021/177) y la Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, y el Fondo Social Europeo (ACIF/2020/173)

TNAP upregulation is a critical factor in Tauopathies and its blockade ameliorates neurotoxicity and increases life-expectancy

Tauopathies are a family of neurodegenerative diseases characterized by the presence of abnormally hyperphosphorylated Tau protein. Several studies have proposed that increased extracellular Tau (eTau) leads to the spread of cerebral tauopathy. However, the molecular mechanisms underlying eTau-induced neurotoxicity remain unclear. Previous in vitro studies reported that the ecto-enzyme tissue-nonspecific alkaline phosphatase (TNAP) dephosphorylate eTau at different sites increasing its neurotoxicity. Here, we confirm TNAP protein upregulation in the brains of Alzheimer's patients and found a similar TNAP increase in Pick's disease patients and P301S mice, a well-characterized mouse model of tauopathies. Interestingly, the conditional overexpression of TNAP causes intracellular Tau hyperphosphorylation and aggregation in cells neighbouring those overexpressing the ectoenzyme. Conversely, the genetic disruption of TNAP reduced the dephosphorylation of eTau and decreased neuronal hyperactivity, brain atrophy, and hippocampal neuronal death in P301S mice. TNAP haploinsufficiency in P301S mice prevents the decreased anxiety-like behaviour, motor deficiency, and increased memory capacity and life expectancy. Similar results were observed by the in vivo pharmacological blunting of TNAP activity. This study provides the first in vivo evidence demonstrating that raised TNAP activity is critical for Tau-induced neurotoxicity and suggest that TNAP blockade may be a novel and efficient therapy to treat tauopathiesThis work was supported by funding from the following: Spanish Ministry of Economy and Competitiveness RTI2018-095753-B-I00 (to M.D.-H.), BFU2016-77885-P (to F.H.) and PGC2018-096177-B-I00 (to J.A.); European Union H2020 program H2020-MSCA-ITN-2017 number 766124 (to M.D-H); European Regional Development Funds from the Comunidad de Madrid S2017/BMD-3700 (NEUROMETAB-CM) (to F.H.); UCM-Santander Central Hispano Bank PR41/17–21,014 (to M.D-H); CIBERNED-ISCIII; and the Fundación R. Areces (to F.H.). A.S-S was hired by RTI2018-095753-B-I00 grant and as postdoctoral researcher by UCM (CT48/19), C.dL. and C.B. were hired by H2020-MSCA-ITN-2017 (grant number 766124), and J M-R had a fellowship from the Fundación La Caixa. This work was supported in part by ERD

P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies

Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2X7 receptors (P2X7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2X7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2X7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2X7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2X7 overexpression caused a significant worsening of Tauinduced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2X7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies

The role of PKD1 in aging-related neurodegeneration: Structural and functional imaging studies

Trabajo presentado en el Second Spanish Molecular Imaging Network (SMIN) Meeting, celebrado en Madrid (España) el 26 de febrero de 2018

Neuroprotective role of PKD1 against ischemic and kainic acid-induced brain injury

Trabajo presentado en el Second Spanish Molecular Imaging Network (SMIN) Meeting, celebrado en Madrid (España) el 26 de febrero de 2018

Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-kappa B/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-kappa B/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders

Forest biomass density across large climate gradients in northern South America is related to water availability but not with temperature

Understanding and predicting the likely response of ecosystems to climate change are crucial challenges for ecology and for conservation biology. Nowhere is this challenge greater than in the tropics as these forests store more than half the total atmospheric carbon stock in their biomass. Biomass is determined by the balance between biomass inputs (i.e., growth) and outputs (mortality). We can expect therefore that conditions that favor high growth rates, such as abundant water supply, warmth, and nutrient-rich soils will tend to correlate with high biomass stocks. Our main objective is to describe the patterns of above ground biomass (AGB) stocks across major tropical forests across climatic gradients in Northwestern South America. We gathered data from 200 plots across the region, at elevations ranging between 0 to 3400 m. We estimated AGB based on allometric equations and values for stem density, basal area, and wood density weighted by basal area at the plotlevel. We used two groups of climatic variables, namely mean annual temperature and actual evapotranspiration as surrogates of environmental energy, and annual precipitation, precipitation seasonality, and water availability as surrogates of water availability. We found that AGB is more closely related to water availability variables than to energy variables. In northwest South America, water availability influences carbon stocks principally by determining stand structure, i.e. basal area. When water deficits increase in tropical forests we can expect negative impact on biomass and hence carbon storage

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study

Background: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. Results: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. Conclusions: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administrationThis study was funded by Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and Instituto de Salud Carlos III (grant nos. RD16/0011/0012 and PI18/ 0371 to I.G.A., grant no. PI19/00549 to A.A., and grant no. SAF2017-82886-R to F.S.-M.) and co-funded by the European Regional Development Fund. The study was also funded by ‘‘La Caixa Banking Foundation’’ (grant no. HR17-00016 to F.S.-M.) and ‘‘Fondos Supera COVID19’’ by Banco de Santander and CRUE. None of these sponsors have had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publicatio