235 research outputs found

    The Blood-Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders

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    With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state of the microvasculature in the brain. When the microvasculature does not function properly, ischemia, hypoxia, oxidative stress and related pathologic processes ensue, further damaging vascular and neural function. One of the most important and specialized functions of the brain microvasculature is the blood-brain barrier (BBB), which controls the movement of molecules between blood circulation and the brain parenchyma. In this review, we are focusing on tight junctions (TJs), the multiprotein complexes that play an important role in establishing and maintaining barrier function. After a short introduction of the cell types that modulate barrier function via intercellular communication, we examine how age, age related pathologies and the aging of the immune system affects TJs. Then, we review how the TJs are affected in age associated neurodegenerative disorders: Alzheimer's disease and Parkinson's disease. Lastly, we summarize the TJ aspects of Huntington's disease and schizophrenia. Barrier dysfunction appears to be a common denominator in neurological disorders, warranting detailed research into the molecular mechanisms behind it. Learning the commonalities and differences in the pathomechanism of the BBB injury in different neurological disorders will predictably lead to development of new therapeutics that improve our life as we age

    Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination.

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    Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.The authors would like to thank the following funding agencies for their support: Paracelsus Medical University PMU-FFF Long-Term Fellowship L-12/01/001-RIV (to and Stand-Alone Grant E-12/15/077-RIT (both to F.J.R.); Chilean ComisiĂłn Nacional de InvestigaciĂłn CientĂ­fica y TecnolĂłgica (CONICYT) FONDECYT Program Regular Grant NÂș 1161787 (to F.J.R.), Regular Grant NÂș 1141015 (to L.F.B.); Chilean CONICYT PCI Program Grant NÂș REDES170233 (to F.J.R.), Grant NÂș REDES180139 and Grant NÂș REDI170037; Chilean CONICYT FONDEFIDeA Program Grant NÂș ID17AM0043 (to M.E.S. and F.J.R.); European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreements N HEALTH-F2-2011-278850 (INMiND) and HEALTH-F2-2011-279288 (IDEA). The work in the KĂŒry laboratory was supported by the German Research Foundation (DFG; KU1934/2_1, KU1934/5-1) and the Christiane and Claudia Hempel Foundation for clinical and iBrain. The work in the Franklin laboratory was supported by grants from the UK Multiple Sclerosis Society and the Adelson Medical Research Foundation, and a core support grant from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. In addition, the present work was supported by the state of Salzburg (to L.A.). We thank Armin Schneider, Sygnis Pharma AG Heidelberg, Germany, for the MBP promoter construct. We disclose any conflict of interest

    Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression

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    Cystatin D is an inhibitor of lysosomal and secreted cysteine proteases. Strikingly, cystatin D has been found to inhibit proliferation, migration, and invasion of colon carcinoma cells indicating tumor suppressor activity that is unrelated to protease inhibition. Here, we demonstrate that a proportion of cystatin D locates within the cell nucleus at specific transcriptionally active chromatin sites. Consistently, transcriptomic analysis show that cystatin D alters gene expression, including that of genes encoding transcription factors such as RUNX1, RUNX2, and MEF2C in HCT116 cells. In concordance with transcriptomic data, quantitative proteomic analysis identified 292 proteins differentially expressed in cystatin D-expressing cells involved in cell adhesion, cytoskeleton, and RNA synthesis and processing. Furthermore, using cytokine arrays we found that cystatin D reduces the secretion of several protumor cytokines such as fibroblast growth factor-4, CX3CL1/fractalkine, neurotrophin 4 oncostatin-M, pulmonary and activation-regulated chemokine/CCL18, and transforming growth factor B3. These results support an unanticipated role of cystatin D in the cell nucleus, controlling the transcription of specific genes involved in crucial cellular functions, which may mediate its protective action in colon cancer

    Using fine-scale spatial genetics of Norway rats to improve control efforts and reduce leptospirosis risk in urban slum environments

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    The Norway rat (Rattus norvegicus) is a key pest species globally and responsible for seasonal outbreaks of the zoonotic bacterial disease leptospirosis in the tropics. The city of Salvador, Brazil, has seen recent and dramatic increases in human population residing in slums, where conditions foster high rat density and increasing leptospirosis infection rates. Intervention campaigns have been used to drastically reduce rat numbers. In planning these interventions, it is important to define the eradication units ‐ the spatial scale at which rats constitute continuous populations and from where rats are likely recolonizing, post‐intervention. To provide this information, we applied spatial genetic analyses to 706 rats collected across Salvador and genotyped at 16 microsatellite loci. We performed spatially explicit analyses and estimated migration levels to identify distinct genetic units and landscape features associated with genetic divergence at different spatial scales, ranging from valleys within a slum community to city‐wide analyses. Clear genetic breaks exist between rats not only across Salvador but also between valleys of slums separated by <100 m—well within the dispersal capacity of rats. The genetic data indicate that valleys may be considered separate units and identified high‐traffic roads as strong impediments to rat movement. Migration data suggest that most (71–90%) movement is contained within valleys, with no clear source population contributing to migrant rats. We use these data to recommend eradication units and discuss the importance of carrying out individual‐based analyses at different spatial scales in urban landscapes

    The democracy of Green Infrastructure

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    With the understanding of nature in terms of ecosystem services and the recognition of the vital role these play for human wellbeing (Millennium Assessment, 2005), the value of the natural realm is scientifically and socially defined while at the same time institutionalised. Within this frame of interpretation, nature is a supplier of provision-ing, regulating, supporting welfare and cultural services, thus becoming not only a life-enabling factor for humanity but also a conceptual construct comparable to cornerstones of democracy, such as equality, freedom and citizenship. The idea of green infrastructure is another recently coined term envisioning nature in cities in the form of a net-work and enabling a broad life-furthering vision of society. Standards for green open spaces embedded in some planning frameworks further state the right for all to a common good. Yet, evidence shows that this common right is not always met. Within the current context of advanced and neoliberal capitalism, green areas are sometimes used as an added financial value for real estate, thus increasing restrictions to their free access and full utilization. In developing countries with young democracies, such as Brazil, this process implies another significant factor of social inequality insofar the restricted access to nature by the poorest people means also diminished food safety, and the jeopardizing of certain cultural practices. In developed countries, loss of land for food production and movements reclaiming the right to the city by squatting unoccupied open spaces to initiate community gar-dens, demonstrates that the access to green spaces is also problematic, although in different ways if compared to developing countries. This chapter contributes to this topic by discussing the inequality in provision of green spaces in informal settlements and social housing development in Brazil, as well as in the globalised north. The chapter concludes with recommendations to enhance democracy through a just provision of nature in cities
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