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 proteinThis study was funded by grants from 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

GSK3 and tau: Two convergence points in Alzheimer's disease

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed. © 2013 The authors and IOS Press. All rights reserved.Peer Reviewe

Microtubule depolymerization and tau phosphorylation

Inge Grundke-Iqbal and Khalid Iqbal found a connection between microtubule associated tau and Alzheimer's disease. They described that abnormally phosphorylated tau is a component of the paired helical filaments found in the disease. Afterwards they described that tau hyperphosphorylation prevents microtubule assembly. Now trying to complement the relationship between microtubules and tau phosphorylation, we have commented on the effect of microtubule disassembly on tau phosphorylation. In this study, we investigated the role of microtubule depolymerization induced by nocodazole on tau phosphorylation in human neuroblastoma SH-SY5Y cells. Our results indicate that nocodazole provokes tau phosphorylation mediated by GSK3, as determined by using AT-8 or Tau-1 antibodies. Interestingly, total GSK3β and GSK3β phosphorylation on Ser-9 are not altered during nocodazole treatment. In addition, microtubule stabilization with taxol had similar effects, likely because taxol and tau compete for the same binding sites on microtubules, and in the presence of taxol, tau could be detached from microtubules. Thus, unbound tau from microtubles can be phosphorylated by GSK3, even if the activity of GSK3 is not altered, probably because tau unbound to microtubules could be a better substrate for the kinase than microtubule-associated tau. These findings suggest that microtubule depolymerization can be a primary event in neurodegenerative disorders like Alzheimer's disease and that tau phosphorylation takes place afterwards. © 2013-IOS Press and the authors. All rights reserved.Peer Reviewe

Glycopeptide resistance in enterococci

The selective pressure resulting from the extensive use of antibiotics over the last 50 years has led to the emergence of bacterial resistance and to the dissemination of resistance genes among pathogenic microorganisms. Consequently, we are now at serious risk of suffering intractable, life-threatening infections. The progressive emergence and rapid dissemination of resistance to glycopeptides, the last resort for treating nosocomial infections with enterococci resistant to usual antibiotics, constitute one of the most dramatic examples of such resistance. Enterococci are normal human commensals, but are also a frequent cause of nosocomial urinary tract infections and nosocomial bacteremia. Enterococcus faecalis causes 80 to 90% of human enterococcal infections, while Enterococcus faecium accounts for most of the remainder. During the last decade, our understanding of the genetics and biochemical basis of resistance to glycopeptides has increased greatly. Furthermore, the application of molecular methods for the diagnosis of glycopeptide-resistant enterococci has provided new insights into the epidemiology of enterococcal infections

Structural study of the compounds formed in the reactions of FeCl3·6H2O with Ni(OH)2 in the presence of dithiolenes HSRSH (R = C6H2Cl2 or C6H4)

In our attempts to prepare coordination polymers by reaction of FeCl3·6H2O and Ni(OH)2 in the presence of dithiolenes HSC6H2X2SH (X = Cl or H), several ion pairs of compounds containing the anionic entity [Ni(SC6H2X2S)2]⁻ were obtained instead. It was also found that other species without dithiolene ligands were formed in these reactions, giving rise to different ion pairs and a tetrametallic cluster. The careful isolation of the different types of crystalline solids allowed the characterization of all of the resulting compounds by single crystal X-ray diffraction (SCXRD). In order to establish the amount of nickel and iron present in the crystals, complementary total reflection X-ray fluorescence (TXRF) analyses were performed. The eight different structural types that were obtained are described and compared with related ones found in the literaturaThis research was funded by the Spanish Ministerio de Economía y Competitividad, grand number (MAT2016-77608-C3-1-P) and Ministerio de Ciencia, Innovación y Universidades (PGC2018-094644-B-C21

GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration

Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.Peer reviewedPeer Reviewe

Novel connection between newborn granule neurons and the hippocampal CA2 field

© 2014 Elsevier Inc. Newborn neurons are continuously added to the hippocampal dentate gyrus (DG) throughout life. Mature and immature granule neurons are believed to send their axonal projections exclusively to the hippocampal CA3 field. However, recent data point to an alternative trisynaptic circuit, involving a direct axonal projection from mature granule neurons to the CA2 field. Whether this circuit takes place only in mature granule neurons or, on the contrary, whether immature granule neurons also contribute to this novel connection is unknown. We used various retroviral vectors to show that immature granule neurons send axonal processes to and establish synaptic contacts with CA2 pyramidal neurons and that axonal growth follows a similar time course to that described for CA3 innervation. In addition, we provide experimental evidence demonstrating that the pathway connecting newborn granule neurons and the CA2 field can be modulated by physiological and deleterious stimuli.Spanish Ministry of Health (SAF 2006-02424, BFU-2008-03980, BFU-2010-21507), the Comunidad de Madrid (SAL/0202/2006), the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) (CB401), and the Fundación R. ArecesPeer Reviewe

LAS EMPRESAS DE BASE TECNOLÓGICA (START-UPS), SINÓNIMO DE INNOVACIÓN, COMPETITIVIDAD E INTANGIBLES. SU IMPORTANCIA EN EL CRECIMIENTO Y DESARROLLO ECONÓMICO. EL CASO DE TABASCO, MÉXICO

Actualmente la innovación tecnológica desempeña un papel fundamental en el mundo empresarial. Esta es la principal característica de las empresas de base tecnológica, más conocidas como Start-ups, mismas que a través de ideas innovadoras y amparadas en las nuevas tecnologías de la comunicación ofrecen soluciones más eficientes a problemas cotidianos, generando empleos y riqueza. Por estas razones, las Start-ups tienen cada vez mayor presencia en el mundo. Por ello se analiza su potencialidad para el desarrollo y crecimiento económico de Tabasco, México. El propósito de la investigación es describir las características de las Start-ups, su potencial para el desarrollo y crecimiento económico y el grado de conocimiento de las mismas, tomando como referencia el personal docente de una institución de educación superior pública. Particularmente, se llevó a cabo una investigación con enfoque cuantitativo y de tipo descriptivo; en su diseño se partió de un universo poblacional constituido por los docentes de la División Académica de Ciencias Económico-Administrativas (DACEA) de la Universidad Juárez Autónoma de Tabasco (UJAT), determinándose un tamaño de muestra de 56 profesores, a quienes se aplicó un cuestionario estructurado a partir del objetivo de la investigación. Los resultados demuestran la potencialidad de las Star-ups para impulsar el desarrollo y crecimiento económico de los países y sus regiones

Neuronal nuclear tau and neurodegeneration

Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging accelerationWork in the laboratory of JA is funded by grants from the Spanish Ministry of Economy and Competitiveness (PGC-2018-09177-B-100). Work in the laboratory of FH is funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España, PID2020-113204GB-I00) and was co-financed from the Comunidad de Madrid through Structural Funds of the European Union [S2017/BMD-3700 (NEUROMETAB-CM)

Frontotemporal dementia-associated N279K tau mutation localizes at the nuclear compartment

Tau is a microtubule-associated protein that plays an important role in Alzheimer’s disease and related tauopathies. Approximately one-half of all cases of Frontotemporal dementia with parkinsonism-17 (FTDP-17) are caused by mutations in the MAPT gene. The N279K mutation is one of the three mutations more prevalent in FTDP-17 cases. Several studies have demonstrated that N279K Tau mutation alters alternative splicing inducing the presence of exon 10. Tau is mainly found in the cytosol of neuronal cells although it has also been localized within the nucleus. Here we demonstrate by biochemical and immunohistochemistry studies in COS-7 cells, that the proportion of mutant N279K Tau increases compared with wild-type at the cell nucleus although cell viability is not affected. These data will provide us with a better outline of the nuclear role of tau protein offering new clues related with this tauopathie.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; SAF-2014-53040-P (JA) and BFU2016-77885- P (FH)), the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII; JA)