Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta

M1 and M2 are the extremes of the differentiation spectrum of activated macrophages. Since microglia are members of the same cell lineage, we have characterized their transcription profile and their phagocytic activity under different conditions. LPS or IFN-gamma induce a M1-like phenotype, while IL-10 or IL-4 differentiate microglia towards a M2-deactivated or M2-alternatively-activated phenotype respectively. These differentiation processes also affect the Notch pathway. In order to study the polarization induced by Abeta, microglia was stimulated with different forms of the peptide. The oligomeric Abeta is a stronger M1-inductor than the fibrillar form. Moreover, a cytokine-induced anti-inflammatory environment reduces the microglial reactivity towards oligomeric Abeta

NF-κB and TNF Affect the Astrocytic Differentiation from Neural Stem Cells

The NF-κB signaling pathway is crucial during development and inflammatory processes. We have previously shown that NF-κB activation induces dedifferentiation of astrocytes into neural progenitor cells (NPCs). Here, we provide evidence  that the NF-κB pathway plays also a fundamental role during the differentiation of NPCs into astrocytes. First, we show that the NF-κB pathway is essential to initiate astrocytic differentiation as its early inhibition induces NPC apoptosis and impedes their differentiation. Second, we demonstrate that persistent NF-κB activation affects NPC-derived astrocyte differentiation. Tumor necrosis factor (TNF)-treated NPCs show NF-κB activation, maintain their multipotential and proliferation properties, display persistent expression of immature markers and inhibit astrocyte markers. Third, we analyze the effect of  NF-κB activation on the main known astrocytic differentiation pathways, such as NOTCH and JAK-STAT. Our findings suggest that the NF-κB pathway plays a dual fundamental role during NPC differentiation into astrocytes: it promotes astrocyte specification, but its persistent activation impedes their differentiation

The epidemiology of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in community-living seniors: protocol of the MemoVie cohort study, Luxembourg

BACKGROUND: Cognitive impairment and Alzheimer’s disease (AD) are increasingly considered a major public health problem. The MemoVie cohort study aims to investigate the living conditions or risk factors under which the normal cognitive capacities of the senior population in Luxembourg (≥ 65 year-old) evolve (1) to mild cognitive impairment (MCI) – transitory non-clinical stage – and (2) to AD. Identifying MCI and AD predictors undeniably constitutes a challenge in public health in that it would allow interventions which could protect or delay the occurrence of cognitive disorders in elderly people. In addition, the MemoVie study sets out to generate hitherto unavailable data, and a comprehensive view of the elderly population in the country. METHODS/DESIGN: The study has been designed with a view to highlighting the prevalence in Luxembourg of MCI and AD in the first step of the survey, conducted among participants selected from a random sample of the general population. A prospective cohort is consequently set up in the second step, and appropriate follow-up of the non-demented participants allows improving the knowledge of the preclinical stage of MCI. Case-control designs are used for cross-sectional or retrospective comparisons between outcomes and biological or clinical factors. To ensure maximal reliability of the information collected, we decided to opt for structured face to face interviews. Besides health status, medical and family history, demographic and socio-cultural information are explored, as well as education, habitat network, social behavior, leisure and physical activities. As multilingualism is expected to challenge the cognitive alterations associated with pathological ageing, it is additionally investigated. Data relative to motor function, including balance, walk, limits of stability, history of falls and accidents are further detailed. Finally, biological examinations, including ApoE genetic polymorphism are carried out. In addition to standard blood parameters, the lipid status of the participants is subsequently determined from the fatty acid profiles in their red blood cells. The study obtained the legal and ethical authorizations. DISCUSSION: By means of the multidisciplinary MemoVie study, new insights into the onset of cognitive impairment during aging should be put forward, much to the benefit of intervention strategies as a whole

Magna Carta, the Rule of Law and the Limits on Government

This paper surveys the legal tradition that links Magna Carta with the modern concepts of the rule of law and the limits on government. It documents that the original understanding of the rule of law included substantive commitments to individual freedom and limited government. Then, it attempts at explaining how and why such commitments were lost to a formalist interpretation of the rule of law from 1848 to 1939. The paper concludes by arguing how a revival of the substantive commitments of the rule of law is central in a project of reshaping modern states

Relativism of Values, science of Law and Legitimacy. Taking a fresh look at the epistemology of Max Weber

L’un des facteurs clés de la relégation du concept de légitimité hors de la science juridique est le relativisme des valeurs, thèse méta-éthique véhiculée notamment par l’école de Vienne. Si l’on est relativiste, on se doit, en tant que scientifique du droit, d’exclure tout propos sur les valeurs. A l’encontre du lien ainsi établi, le présent article entend montrer, à travers un retour à l’épistémologie complexe, et souvent ignorée, de Max Weber, à quelles conditions épistémologiques il est possible, pour un scientifique du droit (du droit constitutionnel), de faire cohabiter ces trois thèmes étroitement associés au nom de Weber que sont le relativisme des valeurs (ce qu’il appelait la « guerre des dieux »), l’idéal de scientificité (associé, dans la vulgate wébérienne, à la notion ambiguë de « neutralité axiologique ») et une approche scientifique de la légitimité. Il s’agit, en quelque sorte, sur fond d’un certain néokantisme partagé par les deux, d’éclairer l’écart qui sépare l’exigence de la « pureté (Reinheit ) » de Kelsen et celle de la « neutralité axiologique (Wertfreiheit) » de Weber.Relativism of values is one of the principal reasons for ruling out the concept of legitimacy from the science of Law : any scientific discourse on Law is expected to exclude any considerations on values. This article proposes a rigorous survey of the complex and much-overlooked epistemology developed by Max Weber. In so doing, the author shows to the contrary that these epistemological conditions allow for the combination, within a science of law, of value-relativism (“the war of the gods”), the scientific ideal, and a scientific discourse on legitimacy. This study thus highlights the common neo-Kantian basis of Kelsen’s Reinheit (“Purity” of Law) and Weber’s Wertfreiheit (“axiological neutrality”), as well as their differences