El receptor P2X7 es una nueva diana terapéutica eficaz para el tratamiento de las tauopatías

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Veterinaria, Departamento de Bioquímica y Biología Molecular, leída el 10-11-2021Tau is a highly soluble microtubule-associated protein (MAP) that in brain is mainly expressed in neurons. Its major role in neurons, especially in axons, is to stabilize the microtubules, regulating their assembly, growing, and shortening in a phosphorylation-dependent way (Buée et al., 2000). The accumulation of hyperphosphorylated tau, with the consequent aggregation into paired helical filaments (PHFs) and formation of neurofibrillary tangles (NFTs), has been described as characteristic feature of a family of neurodegenerative disease collectively known as Tauopathies. This disease family comprises several pathological conditions, including Alzheimer’s Disease (AD), the most common tauopathy, Pick’s disease (PiD), corticobasal degeneration and post-encephalic parkinsonism (Williams, 2006). Tauopathies can show different clinical phenotypes ranging from neuronal loss and reduced synaptic density, with consequent dementia, to behavioural and movement disorders (Lee et al., 2001; Williams, 2006). Although neither the exact causing factors of NFTs aggregation nor the mechanism leading to neuronal and synaptic loss has been elucidated, it has been demonstrated that neuroinflammation is linked to early progression of tauopathies (Metcalfe et al., 2010). Neuroinflammation is an active inflammatory response within the brain characterized by the production of inflammatory mediators and mainly mediated by microglia cells, the innate immune cells of the central nervous system (DiSabato et al., 2016). In addition to inflammatory mediators, other endogenous molecules, known as damage-associated molecular patterns (DAMPs), are secreted from injured cells. These molecules include adenosine triphosphate (ATP), which is released in large amount into the extracellular space during neuroinflammation (Newton and Dixit, 2012)...Tau es una proteína asociada a microtúbulos (MAP) que se expresa principalmente en neuronas. Su función principal en estas células es estabilizar los microtúbulos, especialmente en los axones, regulando su ensamblaje, crecimiento y acortamiento de forma dependiente de fosforilación (Buée et al., 2000). La acumulación de tau hiperfosforilada favorece la agregación de dicha proteína en filamentos helicoidales emparejados (PHF), cuya acumulación desencadena la formación de ovillos neurofibrilares (NFT). Estas estructuras aberrantes intraneuronales se han descrito como rasgo característico de una familia de enfermedades neurodegenerativas conocidas colectivamente como Tauopatías. Esta familia engloba a varias patologías, incluida la enfermedad de Alzheimer (EA), la Tauopatía más común, la enfermedad de Pick (PiD), la degeneración corticobasal y el parkinsonismo posencefálico (Williams, 2006). Las Tauopatías pueden mostrar diferentes signos patológicos que van desde la pérdida neuronal y la reducción de la densidad sináptica, con la consiguiente demencia, hasta trastornos del comportamiento y del movimiento (Lee et al., 2001; Williams, 2006). Aunque todavía se desconocen los factores exactos que causan la agregación de las NFT ni el mecanismo que conduce a la pérdida neuronal y sináptica, se ha demostrado que la neuroinflamación está relacionada con la progresión temprana de las Tauopatías (Metcalfe et al., 2010). La neuroinflamación es una respuesta inflamatoria activa dentro del cerebro caracterizada por la producción de mediadores inflamatorios y principalmente mediada por células de microglia, las células inmunes innatas del sistema nervioso central (DiSabato et al., 2016). Además de los mediadores inflamatorios, las células lesionadas secretan otras moléculas endógenas, conocidas como patrones moleculares asociados al daño (DAMP, acrónimo del inglés damage-associated molecular patterns). Estas moléculas incluyen el adenosín trifosfato (ATP), el cual se puede liberar en gran cantidad al espacio extracelular durante la neuroinflamación (Newton and Dixit, 2012)...Fac. de VeterinariaTRUEunpu

Acne radar: A new intuitive graphic visualization of quality of life in acne patients

Background: There are many instruments available in literature to evaluate the influence of acne on Qualify of Life (QoL), but many of these questionnaires rarely are performed in daily clinical practice. Many of these instruments require a long time for the compilation, and often they are not self completed. There are no simple and intuitive instrument that can be completed by patients alone, with a graphical representation of the results. Objective: To develop a new, rapid and intuitive graphic instrument to a questionnaire allowing both a quick assessment of the impact of acne on patients and, at the same time, increase patient's compliance and self-esteem. Methods: In our study 50 patients were recruited and questionnaire was administered following the main items evaluated in the validated index of QoL from previous studies for acne patients. We have applied an intuitive graph representation, the "Radar Graph", and other statistical methods like the Decisional Map and the Principal Component Analysis, to this questionnaire allowing a quick assessment of the impact of acne on patients. Results: The questionnaire evaluated have 10 items regarding 3 different area: the objective symptoms such as negative perception of their image (imperfection), sting and insomnia; the subjective symptoms such as depression, perception of illness, lack of serenity and shame; and the relational difficulties such as social relationships, working relationships, and intimate relations. The answers are given on a 10-point visual analogue scale. Conclusion: Our survey can be a new, rapid and intuitive graphic instrument to use in clinical practice

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

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

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

Annali storici di Principato Citra, A. 7, n. 1.1 (2009)

A. 7, n. 1.1 (2009): G. Guardia, Editoriale, P. 3 ; R. Salati, Le ambre "tipo Roscigno”, P. 5 ; E. Bianco, La viabilità medievale nel Parco Nazionale del Cilento e Vallo di Diano. Il territorio del Comune di Gioi, P. 33 ; D. Petrone, Le case-torri nel territorio ebolitano, P. 51 ; A. Capano, Pollica e i suoi casali nel Catasto provvisorio del 1815. Il Sessantotto a Salerno. In margine ad un Convegno e ad un libro, P. 69 ; Francesco Sofia, Il '68: alcune riflessioni, P. 95 ; G. Acocella, Un '68 "cattolico"? P. 104 ; P. Cantillo, La profezia di una società estetica, P. 108 ; G. Foscari, Il '68, P. 112 ; M. La Via, Dal mito degli anni '60 alla utopie del '68, P. 113 ; P. Lucia, Miti, utopie, speranze di una generazione, P. 117 ; L. Marinucci, Donne, istituzioni, movimenti civili: una questione ancora attuale. La Mostra "Le frodi alimentari nella provincia di Salerno fra '800 e '900" tenutasi a Salerno il 16 ottobre 2008, a cura di Caterina Aliberti e Francesco Innnella, P. 121 ; C. Aliberti - F. Innella, La Mostra "Le frodi alimentari nella Provincia di Salerno tra Ottocento e Novecento", P. 126 ; I. Ascione, Le frodi alimentari nella provincia di Salerno fra Ottocento e Novecento, P. 128 ; A. Vacca, Inganni cibici, P. 131 ; V. Ferrara, Le attività operative del Comando Carabinieri Politiche Agricole e Alimentari e del Nucleo Antifrodi Carabinieri di Salerno. Il XIV Festival "Linea d'ombra" - Festival culture giovani, P. 134 ; P. D'Antonio, Caos: tra Filosofia, Scienza e Arte, P. 150 ; S. Metetich, Al caos, al caos! Così è (se vi piace), P. 151 ; P. Simone Di Chiara, Il caos, P. 153 ; F.M. Iandiorio, M. Autuori, P.S. Di Chiara, Il caos della natura fra letteratura e percezione, P. 154 ; S. Maritato, D. Di Stefano, A. Di Lauro, M. Massa, Caos e/è cinema, P. 156 ; F. Bonifacio, M. Talento, A. Catoio, Obiettivo caotico, P. 158 ; M. Radano, Per una "memoria" del territorio. Le celebrazioni per il Millenario di Guarrazzano di Stella Cilento (1009-2009), P. 160

SISMIKO:emergency network deployment and data sharing for the 2016 central Italy seismic sequence

At 01:36 UTC (03:36 local time) on August 24th 2016, an earthquake Mw 6.0 struck an extensive sector of the central Apennines (coordinates: latitude 42.70° N, longitude 13.23° E, 8.0 km depth). The earthquake caused about 300 casualties and severe damage to the historical buildings and economic activity in an area located near the borders of the Umbria, Lazio, Abruzzo and Marche regions. The Istituto Nazionale di Geofisica e Vulcanologia (INGV) located in few minutes the hypocenter near Accumoli, a small town in the province of Rieti. In the hours after the quake, dozens of events were recorded by the National Seismic Network (Rete Sismica Nazionale, RSN) of the INGV, many of which had a ML > 3.0. The density and coverage of the RSN in the epicentral area meant the epicenter and magnitude of the main event and subsequent shocks that followed it in the early hours of the seismic sequence were well constrained. However, in order to better constrain the localizations of the aftershock hypocenters, especially the depths, a denser seismic monitoring network was needed. Just after the mainshock, SISMIKO, the coordinating body of the emergency seismic network at INGV, was activated in order to install a temporary seismic network integrated with the existing permanent network in the epicentral area. From August the 24th to the 30th, SISMIKO deployed eighteen seismic stations, generally six components (equipped with both velocimeter and accelerometer), with thirteen of the seismic station transmitting in real-time to the INGV seismic monitoring room in Rome. The design and geometry of the temporary network was decided in consolation with other groups who were deploying seismic stations in the region, namely EMERSITO (a group studying site-effects), and the emergency Italian strong motion network (RAN) managed by the National Civil Protection Department (DPC). Further 25 BB temporary seismic stations were deployed by colleagues of the British Geological Survey (BGS) and the School of Geosciences, University of Edinburgh in collaboration with INGV. All data acquired from SISMIKO stations, are quickly available at the European Integrated Data Archive (EIDA). The data acquired by the SISMIKO stations were included in the preliminary analysis that was performed by the Bollettino Sismico Italiano (BSI), the Centro Nazionale Terremoti (CNT) staff working in Ancona, and the INGV-MI, described below

Le attività del gruppo operativo INGV "SISMIKO" durante la sequenza sismica "Amatrice 2016",

SISMIKO è un gruppo operativo dell’Istituto Nazionale di Geofisica e Vulcanologia (INGV) che coordina tutte le Reti Sismiche Mobili INGVPublishedLecce3T. Sorgente sismica4T. Sismicità dell'Italia8T. Sismologia in tempo reale1SR TERREMOTI - Sorveglianza Sismica e Allerta Tsunami2SR TERREMOTI - Gestione delle emergenze sismiche e da maremoto3SR TERREMOTI - Attività dei Centr

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types