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

Tau-knockout mice show reduced GSK3-induced hippocampal degeneration and learning deficits

It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic mice that overexpress GSK3β in forebrain regions including dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that GSK3 overexpression results in DG degeneration. To test whether tau protein modified by GSK3 plays a role in that neurodegeneration, we have brought GSK3 overexpressing mice to a tau knockout background. Our results indicate that the toxic effect of GSK3 overexpression is milder and slower in the absence of tau. Thus, we suggest that the hyperphosphorylated tau mediates, at least in part, the pathology observed in the brain of GSK3 overexpressing mice.This work was supported by grants from Spanish Plan Nacional, Comunidad de Madrid, Fundación Botín, CIBERNED, and an institutional grant from Fundación Ramón Areces.Peer reviewe

Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 ± 27 nM), in an ATP-competitive manner (K i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 μM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3β protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by β-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.Supported by grants from the Comunidad de Madrid, the Fundacion “La Caixa,” the Lilly Foundation, the Spanish Comision Interministerial de Ciencia y Tecnologia, and an institutional grant from the Fundacion Ramon Areces.Peer reviewe

Assessing population exposure to phthalate plasticizers in thirteen Spanish cities through the analysis of wastewater

Phthalates are widely used plasticizers that produce endocrine-disrupting disorders. Quantifying exposure is crucial to perform risk assessments and to develop proper health measures. Herein, a wastewater-based epidemiology approach has been applied to estimate human exposure to six of the mostly used phthalates within the Spanish population. Wastewater samples were collected over four weekdays from seventeen wastewater treatment plants serving thirteen cities and ca. 6 million people (12.8 % of the Spanish population). Phthalate metabolite loads in wastewater were transformed into metabolite concentrations in urine and into daily exposure levels to the parent phthalates. Considering all the sampled sites, population-weighted overall means of the estimated concentrations in urine varied between 0.7 ng/mL and 520 ng/mL. Very high levels, compared to human biomonitoring data, were estimated for monomethyl phthalate, metabolite of dimethyl phthalate. This, together with literature data pointing to other sources of this metabolite in sewage led to its exclusion for exposure assessments. For the remaining metabolites, estimated concentrations were closer to those found in urine. Their 4-days average exposure levels ranged from 2 to 1347 μg/(day∙inh), exceeding in some sites the daily exposure thresholds set for di-i-butyl phthalate and di-n-buthyl phthalate by the European Food Safety Authority.Financial support. This study was supported by MCIU/AEI (projects CTM2016-81935-REDT, CTM2017-84763-C3-1-R, CTM2017-84763-C3-2-R, CTM2017-84763-C3-3-R, and CEX2018-000794-S), Galician Council of Culture, Education and Universities (ED481D 2017/003 and ED431C2017/36), Generalitat Valenciana (projects Prometeo/2018/155 and Prometeo/2019/040) and Universitat Jaume I (project UJI-B2018-55). Several of the above mentioned projects are cofunded by FEDER/ERDF. Sampling, sample and data provision and/or analytical support: Viaqua and Concello de Santiago de Compostela, EMAYA (Palma), Jordi Palatsi from Aqualia (Lleida WWTP), Cristian Mesa and Angela Vidal from Aigues de Barcelona (Barcelona WWTP), Iñigo González (Consorcio de Aguas de Bilbao-Bizkaia), the Public Entity of Wastewater Treatment (EPSAR) of the Generalitat Valenciana and especially Fernando Llavador. Luis Aceiton, Enrique Albors, Angel Jiménez, Maria José Tarrega, Sonia Tristante and all the personal of the WWTPs (Aguas de Valencia, Spain), are acknowledged for their help with the sampling. Sociedad de Fomento Agrícola Castellonense (FACSA, Castellon), and especially WWTP operators Santiago Querol and Sara Gargallo are acknowledged for providing wastewater samples from Castellón, as well as Subdirección General de Gestión del Agua, Ayuntamiento de Madrid, for allowing the collection of samples from Madrid centro.Peer reviewe

Aging and Brain Deterioration

Carlos Dotti and Vicente Rodríguez (coordinators).Advanced age significantly increases the risk of developing chronic diseases such as cancer, diabetes, cardiovascular, immune and mental disease. Regarding the latter, advanced age is a necessary factor for the development of non-hereditary forms of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Despite years of intense research, we still do not know how these diseases occur, this being one of the main reasons for the lack of adequate interventions to prevent or cure these pathologies. To overcome the current limitations in the field, we plan to: 1) generate basic knowledge on the mechanisms responsible for cognitive, behavioral, motor, metabolic and sociability disorders that occur with age, 2) define the mechanisms that determine individual susceptibility to neurodegeneration, 3) design and develop strategies to improve brain aging, and 4) explore social and environmental conditions of the older population to know their influence in brain degeneration. Individual, social and policy interventions must be considered for future research.Peer reviewe

Propagation of tau via extracellular vesicles

Extracellular vesicles (EVs), like exosomes, play a critical role in physiological processes, including synaptic transmission and nerve regeneration. However, exosomes in particular can also contribute to the development of neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease, and prion diseases. All of these disorders are characterized by protein aggregation and deposition in specific regions of the brain. Several lines of evidence indicate that protein in exosomes is released from affected neurons and propagated along neuroanatomically connected regions of the brain, thus spreading the neurodegenerative disease. Also, different cell types contribute to the progression of tauopathy, such as microglia. Several groups have reported tau release via exosomes by cultured neurons or cells overexpressing human tau. Although the exact mechanisms underlying the propagation of protein aggregates are not fully understood, recent findings have implicated EVs in this process. The AD brain has two hallmarks, namely the presence of amyloid-β-containing plaques and neurofibrillary tangles, the latter formed by hyperphosphorylated tau protein. Both amyloid peptide and tau protein are present in specific exosomes. This review summarizes recent advances in our understanding of exosomes in the pathology of AD, with a special focus on tau protein.Spanish Ministry of Science, Innovation and Universities (BFU2016-77885-P), the Comunidad de Madrid, through EU structural funds (S2017/BMD-3700 NEUROMETAD-CM), CIBERNED (ISCIII), and the Fundacion Ramon Arece

Tauopathies

Tau is a microtubule-associated protein predominantly expressed in nerve cells that promote microtubule assembly and microtubule stabilization. Tau is a cytosolic protein mainly present in axons and involved in anterograde axonal transport. In several neurodegenerative diseases, as for example Alzheimer’s disease, tau metabolism is altered. Thus, alterations in the amount of the tau protein, missense mutations, posttranscriptional modifications like phosphorylation, aberrant tau aggregation or a different expression of some of its isoforms could provoke pathological effects resulting in the appearance of neuronal disorders known as tauopathies. The purpose of this work is to review the possible mechanisms for tau alterations that could lead to the onset of tau pathology. First we will focus on tau turnover, then on tau phosphorylation and, finally, on tau aggregation.This work was supported by grants from the Fundacion La Caixa, Neuropharma, Fundacion Botin, Spanish CICYT, Comunidad de Madrid (NEURODEGMODELS-CM), CIBER on Neurodegeneration and by institutional grants from the Fundacion Ramon Areces and from the Fondo de Investigaciones Sanitarias.Peer reviewe

Commentary: Genome-wide association study identifies 74 loci associated with educational attainment

descripción no proporcionada por scopusThis work was supported by grants from the following entities: Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0066, Spain); the Spanish Ministerio de Economía y Competitividad (grants SAF 2015-66603-P, BFU2016-77885-P, and BUF2013-40664-P).Peer Reviewe

Intra and extracellular protein interactions with tau

Tau is a sticky protein mainly expressed by neurons, which may be found in different subcellular fractions or outside the cell. Tau is mainly associated to microtubules in the cytoplasm, although besides tubulin, tau can also bind to other proteins and to itself to form different polymers, some of which are relevant in pathological disorders. In this short review, we have revised some of the interactions involving tau, both inside or outside of the cell. Different regions of tau are involved in these interactions and some of them are more conserved throughout evolution than others.Peer reviewe

ACE2 is on the X chromosome: could this explain COVID-19 gender differences?

This commentary refers to ‘Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors’, by I.E. Sama et al., 2020;41:1810–1817. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease termed coronavirus disease 2019 (COVID-19) shows a fatality rate greater in men compared with women.1 To explain this, some hypotheses have been raised, from genes that regulate the immune system encoded on the X chromosome to smoking behaviour,2 to expression levels1 or variants for angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2.3However, we would like to point out that the ACE2 gene is located on the X chromosome (location: Xp22.2; nucleotides 15 494 402–15 602 148, GRCh38.hg38 version). To our knowledge, the importance of ACE2 localization on the X chromosome has not been explored previously. Often, to have two copies ameliorates the deleterious effects of X-linked diseases and, as a consequence, most X-linked syndromes produce male diseases.Funded by Autonoma University and Hospital Clínico San Carlos (employer).Peer reviewe