In dieser Arbeit werden die Zerfälle des schwersten bekannten Leptons, des Tau, in die beiden leichteren Leptonen, Elektron oder Muon, untersucht. Die durch Elektron-Positron-Annihilation am LEP-Speicherring entstehenden Tau-Paare werden ausgewertet, um die Verzweigungsverhältnisse B_{l=e,\mu} = \frac{\Gamma(\tau\to\nu_\tau l\bar{\nu}_l)}{\Gamma_{tot}} zu bestimmen. Die Analyse erfolgt für die gesamte bei LEP~I mit dem L3-Detektor auf der Z-Resonanz aufgezeichnete Datenmenge. Aus über 160000 selektierten Tau-Zerfällen werden die leptonischen Zerfälle identifiziert und die leptonischen Verzweigungsverhältnisse gemessen: B_e = (17.806 \pm 0.104_{stat} \pm 0.076_{sys}) B_\mu = (17.342 \pm 0.110_{stat} \pm 0.067_{sys}) Das daraus bestimmte Verhältnis der Kopplungen von Elektron und Muon im geladenen schwachen Strom \frac {g_\mu}{g_e} = 1.0007 \pm 0.0051 stimmt ausgezeichnet mit der aus dem Standardmodell entsprechend der angenommenen Lepton-Universalität erwarteten Gleichheit der Kopplungen überein. Durch Vergleich der Verzweigungsverhältnisse mit der im Stan dardmodell berechneten leptonischen Zerfallsbreite \Gamma (\tau\to\nu_\tau l\bar{\nu}_l) wird ein Wert für die Tau- Lebensdauer bestimmt, der mit der direkten Messung sehr gut verträglich ist. Unter Hernahme der direkten L3-Messung der Tau-Lebensdauer wird die Universalität der Kopplungen am Wl\bar{\nu}_l-Vertex für g_\tau/g_\mu und g_\tau/g_e mit einer Genauigkeit von 6 Promille bestätigt. Aus dem Verhältnis der hadronischen zur leptonischen Zerfallsbreite des Tau wird die Kopplungskonstante der starken Wechselwirkung gemessen: \alpha_s(m_\tau)=0.324~\ pm~0.009_{Experiment}~\pm~0.017_{Theorie}Der daraus zur Masse des Z-Bosons extrapolierte Wert\alpha_s(m_\mathrm{Z}) = 0.1191~\pm~0.0009_{Experiment}~\pm~0.0019_ {Theorie}ist in exzellenter Übereinstimmung mit den direkten Messungen und bestätigt die von der QCD vorhergesagte Energieabhängigkeit der Kopplungskonstante. Die Masse m_{\nu_\tau} des Tau-Neutrinos läßt sich aus dem Vergleich der gemessenen mit einer für m_{\nu_\tau} berechneten leptonischen Zerfallsbreite begrenzen auf:m_{\ nu_ \tau} < 107 MeV (mit 95% Wahrscheinlichkeit)\end {eqnarray*} Das Verhältnis aus B_\mu und B_e ist sensitiv auf die Kopplungen an ein geladenes Higgs-Dublett und liefert eine Grenze für die Masse des geladenen Higgs-Bosons von m_{H^{\pm}} > 1.0 \tan \beta GeV (mit 95% Wahrscheinlichkeit) Hierbei ist \tan \beta das Verhältnis der Vakuumerwartungswerte beider Higgs-Dubletts. / This is a study of the decays of the heaviest known lepton, the tau, into the two lighter leptons, electron or muon. From tau pairs produced at the LEP storage ring in electron-positron annihilation the leptonic branching fractions of the tau, B_{l=e,\mu}=\frac{\Gamma(tau\to\nu_tau l\bar{\nu}_l)}{\Gamma_{tot}}, are measured. The analysis was performed using the full LEP I data sample collected with the L3 detector at centre-of-mass energies around the Z mass. Within about 160000 selected tau decays the leptonic decays were identified and the branching fractions are measured as: B_e = (17.806 \pm 0.104_{stat} \pm 0.076_{sys})B_\mu = (17.342 \pm 0.110_{stat} \pm 0.067_{sys}). It is used to test the electron-muon universality in the weak charged current couplings: \frac {g_\mu}{g_e} = 1.0007 \pm 0.0051 . The ratio of the couplings of electron and muon is in excellent agreement with the Standard Model assumption of 1. Using the Standard Model prediction for the leptonic decay width, \Gamma(tau\to\nu_tau l\bar{\nu}_l), the tau lifetime is determined, precisely confirming direct measurements. Together with the L3 measurement of the tau lifetime the universality in the couplings at the Wl\bar{\nu}_l vertex is verified for g_tau/g_\mu and g_tau/g_e at a level of 6 permille. The ratio of hadronic to leptonic tau decay width, R_tau, is calculated from the measured leptonic branching fractions, and a value of the QCD coupling constant is extracted:\alpha _s(m_tau) = 0.324~\pm~0.009_{exp}~\pm~0.017_{theory}. The value obtained by evolving \alpha_s(m_tau) to the Z mass, \alpha_s(m_\z)= 0.1191~\pm~0.0009_{exp}~\pm~0.0019_{theory}, agrees very well with direct measurements and confirms the predicted running of \alpha_s. An upper limit for the mass of the tau neutrino, m_{\nu_{tau}}, is estimated from a comparison of the measured leptonic tau decay rate to a prediction as a function of m_{\nu_tau}: m_{\nu_tau} < 107 MeV (at 95% confidence level) The ratio of B_\mu to B_e is sensitive to the couplings to a charged Higgs doublet and allows to set a limit on the mass of the charged Higgs boson m_{H^{\pm}} > 1.0 \tan \beta GeV (at 95\% confidence level), where \tan \beta is the ratio of the vacuum expectation values of the two Higgs doublets.

A doença de Alzheimer (DA) é uma patologia neuropsiquiátrica caracterizada por perda cognitiva, com marcante déficit de memória desde o estágio inicial, degeneração neuronal progressiva, e constitui a principal causa de demência no mundo. Além disso, a DA é frequentemente agravada pela ocorrência de comorbidades. Dados epidemiológicos apontam para uma importante associação clínica entre a DA e a epilepsia. A ausência de um modelo de estudo relevante, entretanto, tem impedido o avanço do entendimento dos mecanismos moleculares que subjazem essa comorbidade. A cepa Wistar Audiogenic Rat (WAR) tem sido amplamente utilizada como modelo animal para o estudo de epilepsia e, recentemente, déficits de memória foram relatados em animais desta cepa, o que suscitou a possibilidade de constituírem um modelo experimental para o estudo da comorbidade entre DA e epilepsia. No presente estudo, foi avaliado o desempenho de WAR adultos em diferentes idades no teste de memória do labirinto aquático de Morris (LAM). Realizaram-se ainda análises bioquímicas e de imunoistoquímica dos principais biomarcadores celulares da DA, o peptídeo beta-amiloide (A?) e a proteína Tau hiperfosforilada (pTau), no hipocampo e no córtex pré-frontal de WAR e Wistar de idades pareadas. No LAM, os WAR de 9 meses apresentaram déficit de aprendizagem e de retenção de memória (24 horas após o treinamento), quando comparados aos Wistar de idade pareada, enquanto que aos 12 meses, os WAR apresentaram apenas déficit de aprendizagem. Os animais WAR de 12 meses apresentaram também aumento significativo nos níveis de pTau e Tau total em extratos de hipocampo, quando comparados aos Wistar controles de mesma idade, o que não foi observado para os extratos de córtex pré-frontal. Os WAR também apresentaram elevação idade-dependente nos níveis e distribuição anormal de pTau em algumas sub-regiões hipocampais, como avaliado por imunoistoquímica. Não foi possível quantificar A? endógeno por meio das estratégias utilizadas. Quando analisados em conjunto, os dados sugerem que os déficits de memória observados nos WAR podem ser reflexo da hiperfosforilação e consequente distribuição anormal da proteína neuronal Tau, por um mecanismo molecular a ser desvendado. Não foi possível, ainda, determinar se este mecanismo inclui aumento nos níveis de agregados de A?, como esperado em modelos de DA. Portanto, o emprego de cepa WAR como modelo experimental para o estudo dos fenômenos moleculares subjacentes à comorbidade entre epilepsia e doença de Alzheimer, embora promissor, ainda precisa ser melhor caracterizado. / Alzheimer disease (AD) is a neuropsychiatric disorder characterized by cognitive loss, marked memory deficit since the early stage, progressive neuronal degeneration, and it is the leading cause of dementia around the world. In addition, AD is often aggravated by the occurrence of comorbidities. Epidemiological data point to a clinical association between AD and epilepsy. The absence of a relevant model, however, has impaired the advance of the understanding about the molecular mechanisms that underlie this comorbidity. The Wistar Audiogenic Rat (WAR) strain has been widely used as an animal model to the study of epilepsy. Recently, memory deficits have been reported in WARs, which has raised the possibility that this strain may represent an experimental model to the study of comorbidity between AD and epilepsy. Here we evaluated the performance of WARs in the reference memory test Morris water maze (MWM) at different ages. Biochemical and immunohistochemical analyzes of the main AD biomarkers, beta-amyloid peptide (A?) and hyperphosphorylated Tau protein (pTau), were also performed in the hippocampus and prefrontal cortex of age-matched WARs and Wistar controls. In the LAM, middle-aged (9 months) WARs presented learning and memory retention deficits (24 hours after training session) when compared to age-matched Wistar rats, whereas at 12 months, WARs presented only learning deficits. Adult WAR animals showed a significant increase in the levels of pTau and total Tau in hippocampal extracts, when compared to Wistar controls, which was not observed in prefrontal cortex extracts. WARs also showed higher levels and abnormal distribution of pTau in some hippocampal subregions, as assessed by immunohistochemistry. It was not possible to detect endogenous A? by the strategies used. Taken together, these data suggest that memory deficits observed in WARs may be a consequence of hyperphosphorylation and consequent abnormal distribution of Tau triggered by a molecular mechanism yet to be identified. It has not yet been determined whether this mechanism includes increased levels of A? aggregates, as expected in AD models. Therefore, the use of the WAR strain as an experimental model to the study of the molecular phenomena underlying the comorbidity between epilepsy and Alzheimer disease, although promising, still needs to be further characterized.

High prevalence of individuals with autism spectrum disorder (ASD) and the legislation movement impacted the placement of students with ASD in general education settings. Hence, the increase raised the need to conduct research for ASD populations, and to examine the effectiveness of these interventions. With the increase of single case-design (SCD) studies, there is a demand to include SCD in the evaluation of evidence- based practices (EBPs), to analyze and interpret SCD results in meaningful ways beside visual analysis, and to generate effect size estimates. This dissertation contains four systematic literature reviews which examine single-case intervention research targeting academic, social communication, play, and functional life skills for children with ASD in school settings. 132 studies with 924 AB phase contrasts were analyzed using visual analysis and three non-overlap measures. Sensitivity and specificity of Tau-U, IRD, and Baseline Corrected Tau were tested on detecting intervention effects. Also, the three methods were examined in their agreement with interpretations based on the visual analysis and the effect of confounding factor on their scores. The analysis demonstrated that the three methods performed fairly well in distinguishing effective from non-effective interventions. The three non-overlap methods had a moderate to substantial level of agreement with visual analysis. The author recommended further research on the impact of confounding factors especially baseline trend and autocorrelation as well as the use of effect size methods with high sensitivity and visual aids to improve the reliability and accuracy of visual analysis.

Reg-1α est une protéine essentielle du système digestif impliquée dans des fonctions de prolifération, différenciation et régénération. Elle est exprimée et sécrétée par les neurones du système nerveux central où elle stimule la croissance neuritique et régule la différenciation et la migration des cellules précurseurs neurales via son récepteur EXTL3 et la voie GSK-3β. Par ailleurs, Reg-1α est surexprimée dans les cerveaux de patients Alzheimer et nos études préliminaires montrent qu’elle est associée à Tau hyperphosphorylée. Nous avons étudié dans ce contexte (1) le rôle de Reg-1α dans les processus neurodégénératifs liés à Tau et les voies de signalisation impliquées et (2) sa localisation dans le cerveau de souris transgéniques exprimant Tau mutée P301L/R406W. Nous avons montré que la surexpression de Reg-1α dans des neurones différenciés ne modifie pas significativement la voie Akt/GSK-3β/P-Tau mais induit la formation d’amas de Tau anormalement phosphorylée et une perturbation modérée du transport axonal. Par contre, sur des neurones surexprimant TauP301L, Reg-1α stimule la phosphorylation de Tau via Akt/GSK-3β entrainant la formation accentuée de renflements neuritiques et la perturbation sévère du transport axonal. In vivo, Reg-1α augmente avec l’âge dans le cerveau des souris contrôles et son expression est plus importante dès 5 mois chez les souris PLB2 Tau comparée aux souris sauvages. De plus, Reg-1α est associée à l’accumulation de Tau phosphorylée en S202 chez les souris transgéniques. Reg-1α est une protéine pouvant moduler l’hyperphosphorylation de Tau et le transport axonal et donc pourrait jouer un rôle dans le développement des tauopathies. / Reg-1α is an essential protein of the digestive system involved in proliferation, differentiation and regeneration functions. It is also expressed and secreted by neurons of the central nervous system where it stimulates neurite outgrowth and regulates differentiation and migration of neural precursor cells via its receptor EXTL3 and GSK-3β pathway. Moreover, Reg-1α is overexpressed in the brain of Alzheimer's patients and our preliminary studies show that it is associated with hyperphosphorylated Tau. We studied in this context (1) the role of Reg-1α in neurodegenerative processes associated with Tau and the involved signaling pathways and (2) its location in the brain of transgenic mice expressing mutated Tau P301L/R406W (PLB2 mice). We showed that overexpression of Reg-1α in differentiated neurons does not significantly modify the Akt/GSK-3β/P-tau pathway. However it induces the formation of neuritic swellings associated with abnormal phosphorylated Tau and leads to the disruption of axonal transport. Furthermore, in neurons overexpressing TauP301L, Reg-1α overexpression stimulates Tau phosphorylation via Akt/GSK-3β regulation and results in the increase of neuritic bulges and severe disruption of axonal transport. In vivo, Reg-1α expression increases with age in brains of control mice and is already higher in 5 month-old PLB2 Tau mice compared with age-matched controls. Cellular localization showed that Reg-1α is associated with the accumulation of phosphorylated Tau S202 in PLB2 mice. Finally, Reg-1α can regulate Tau hyperphosphorylation and axonal transport and consequentely could be involved in Tauopathy development.

La maladie d’Alzheimer (MA) est une maladie multifactorielle et à ce jour aucune cause des formes sporadiques de la maladie, qui représente plus de 99% des cas, n’a été mise en évidence. Des données émergentes de la littérature suggèrent l’existence d’un lien entre les dysfonctionnements thyroïdiens et la MA. Dans ce contexte, l’objectif de cette étude était de préciser l’implication de l’hypothyroïdie dans les processus neuropathologiques de la MA. En utilisant un modèle de rats rendus hypothyroïdiens par un traitement au propylthiouracile (PTU), nous avons montré que l’hypothyroïdie favorise la mise en place de lésions caractéristiques de la MA dans l’hippocampe, structure du cerveau précocement altérée dans la maladie et qui joue un rôle crucial dans les processus de mémoire. Une étude d’IRM in vivo a révélé une diminution progressive du volume cérébral des rats hypothyroïdiens. Dans l’hippocampe, l’hypothyroïdie s’accompagne d’une augmentation de la production de peptides amyloïdes, d’une hyperphosphorylation de la protéine Tau et d’une augmentation de la libération de plusieurs cytokines pro-Inflammatoires. Ces lésions, caractéristiques de la MA, sont associées à des troubles de la mémoire spatiale à court et long terme et à une altération de deux voies de signalisation connues pour jouer un rôle important dans les processus de plasticité synaptique et de mémoire : la voie calcique et la voie ERK-MAPK. Afin d’évaluer le potentiel de restauration de ces lésions, une partie des rats hypothyroïdiens a reçu des injections intra-Péritonéales de triiodothyronine (T3), forme active des hormones thyroïdiennes. Nos résultats montrent que l’administration de T3 permet de restaurer les déficits de mémoire spatiale à court terme, mais pas à long terme. En outre, ce même traitement permet de restaurer les niveaux de cytokines pro-Inflammatoires, de peptides amyloïdes ainsi que les voies « calcique » et « ERK-MAPK ». Ces données renforcent l’existence d’un lien entre l’hypothyroïdie et la MA : elles suggèrent que l’hypothyroïdie pourrait représenter un facteur important pouvant impacter le risque de développer des formes sporadiques de la MA. / Alzheimer’s disease (AD) is a multifactorial disease and to date no single cause for the sporadic forms, which accounts for over 99% of the cases, has been established. Converging evidence suggests a possible link between thyroid dysfunctions and AD. The aim of the present study was to explore the possibility that adult hypothyroidism represents an etiopathogenic mechanism of AD. In this context, using a hypothyroid rat model induced by propylthiouracil (PTU) treatment, we report that hypothyroidism is associated with several AD-Associated hallmarks in the hippocampus, a brain structure affected in early stages of AD and which plays a crucial role in memory processes. In vivo MRI revealed a progressive decrease in cerebral volume of hypothyroid-Rats. In the hippocampus, hypothyroidism resulted in Tau hyperphosphorylation, increased levels of amyloid peptide and of several pro-Inflammatory cytokines. These AD-Related pathological hallmarks were associated with impaired short- and long-Term spatial memory and alteration of hippocampal signalling pathways important for synaptic plasticity and memory, including calcium and ERK-MAPK pathways. To test the potential reversion of PTU-Induced lesions, we injected hypothyroid rats with triiodothyronine (T3), the active form of thyroid hormone. Our results show that intraperitoneal injections of T3 restored spatial short-Term, but not long-Term memory in hypothyroid-Treated rat. Furthermore, levels of pro-Inflammatory cytokines, amyloid peptide and of proteins involved in calcium and ERK-MAPK signalling were restored. These data strengthen the link between hypothyroidism and AD, supporting the idea that hypothyroidism may represent an important factor impacting the risk for developing sporadic forms of AD.

Pathogenesis, diagnosis and treatment, the essential domains in medical practice, seem helpless to address Alzheimer's disease (AD). With a huge mortality rate, it is looming and threatening the socioeconomic barrier. Despite many different studies, the pathogenesis of AD remains inconclusive. However, growing numbers of studies suggest oxidative stress to contribute to the initiation and progression of AD. We propose an iron hypothesis: iron mediated oxidative damage by reactive oxygen species (ROS), which induces protective roles of amyloid beta and hyper-phosphorylated tau (HP-tau) to sequester iron and limit the disease. We propose to study such mechanism using transgenic mice models for AD, inducing oxidative stress to elevate intracellular iron, and analyze its co-localization with proteins using Magnetic Resonance Imaging (MRI), 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Western blot. We report three primary findings: 1) a significant loss in T2 signal over bilateral hippocampi of transgenic mice compared to the wild types (WT) by three months, corresponding to early disease and the ability of proteins to sequestration iron. Ability of rescue treatments to impede disease progression reflected as preserved T2 signal intensities over these areas throughout our study period of nine months. 2) Concentration of zinc and its dual role in the presence or absence of oxidative stress reflected as loss of 1H NMR T2 measurement showed that higher concentrations of zinc were neuro protective when there was an active oxidative stress inducing condition, but neurotoxic and promote oxidative damage in normal condition. And 3) Different strains of mice, according to their transgene, expressed various proteins associated with AD. However, these expressions were in accordance with our iron-hypothesis.

Tauopathy, which results from the oligomerization of misfolded tau protein in neurons, is a feature present in a number of neurodegenerative diseases and a hallmark of Alzheimer’s Disease (AD). Tau is an important phosphoprotein that regulates the assembly of microtubules, but tauopathy can occur when tau becomes hyperphosphorylated. Phosphorylation prevents tau from binding to tubulin, which results in cytosolic accumulation of tau and eventual oligomerization. This abnormal accumulation of tau leads to the spreading of hyperphosphorylated tau to downstream synaptically connected neurons through an unknown mechanism. In AD, the hippocampus is one of the first brain structures to be affected by tauopathy in humans. According to previous research, tauopathy occurs primarily between principal cells in the hippocampus. The involvement of local inhibitory interneurons in tauopathy and their potential role in AD is more controversial. Previous research suggests that tau pathogenesis primarily affects principal cells; however, given the importance, diversity, and function of interneurons in the hippocampus, it is important to gain a better understanding of the interneuron subtypes that may be impacted by the spread of trans-synaptic tau into the hippocampus. Understanding the involvement of interneurons in trans-synaptic tau transmission is important to understanding neurodegeneration in AD and other neurodegenerative disorders. To investigate this, both male and female genetically-modified mice underwent surgery to examine the trans-synaptic spread of pathogenic tau (EGFP-Tau P301L) from the entorhinal cortex to hippocampal neurons. Histology and imaging analysis of brain sections were performed to examine the hippocampal cells impacted by trans-synaptic spread of tau. Results show that pathogenic tau can trans-synaptically spread from presynaptic neurons in the entorhinal cortex into downstream hippocampal interneurons and also that hippocampal interneurons are capable of trans-synaptically spreading tau. Future studies examining the specific subtypes of hippocampal interneurons vulnerable to trans-synaptic spread of tau will be important for a better understanding of disease progression, which could lead to uncovering new therapeutic targets for neurodegenerative diseases, like AD, which are associated with tauopathy.

La maladie d’Alzheimer à forme tardive, exempte de mutations, représente près de 99% des 850 000 cas répertoriés en France. Hormis l’âge, des facteurs génétiques comme BIN1 apparaissent déterminant dans l’établissement de l’amyloïdopathie et de la tauopathie, marqueurs constitutifs de cette maladie. Le travail de thèse est basé sur l’étude d’une surexpression du gène humain de BIN1 et de son impact dans un contexte murin de tauopathie. La surexpression seule de BIN1 entraine des défauts mnésiques à court terme associés à des anomalies cellulaires et moléculaires au niveau de la voie temporo-hippocampique. Ces altérations sont exacerbées par la combinaison de la souris TgBIN1 avec le modèle de tauopathie, à la fois chez les mâles et les femelles. Pour autant il apparait que la surexpression de BIN1 préserve la mémoire spatiale dépendamment de l’âge et du sexe. L’hippocampe apparait en grande partie préservé des inclusions intracellulaires de Tau et la myéline des fibres axonales est retrouvé intacte. Ces éléments mettent en évidence que BIN1 est un acteur important dans l’établissement de la tauopathie et que son activité neuro-protectrice peut être médiée par un complexe moléculaire direct impliquant à la fois Tau et RNT4-A/Nogo-A. / Late Onset Alzheimer Disease represents more than 99% of total Alzheimer cases and it is not caused by genetic mutations. Among risk factors such as age, genetic compounds as BIN1 appear to be determinant for the pathological process establishment. This study aims to determine the BIN1 overexpression effect in mice and in a tauopathy context. In this study, BIN1 overexpression alone caused short term memory impairments linked with the cellular and molecular abnormalities. These disorders are exacerbated by a combination of TgBIN1 mice with a tauopathy model, both in males and females. Surprisingly, BIN1 overexpression rescued long term and spatial memory regarding the age and sex. Hippocampus appeared to be preserved from intracellular Tau inclusions. Moreover, fornix myelin is found intact. These elements highlighted BIN1 which is a key gene in tauopathie establishment. BIN1 neuroprotective activity is mediated by direct molecular interactions both with Tau and RTN4-A/Nogo-A.

Thesis (M.S.W.)--University of Hong Kong, 1979.

No description available.