Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of protective neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.

Rôle de la protéine-associée aux microtubules MAP2 dans l'acquisition et le maintien du phénotype neuronal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Immunity and Arginine Deprivation in Alzheimer's Disease

The pathogenesis of Alzheimer’s disease (AD) is a critical unsolved question, and while recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by pro-inflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c+ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

There is a large interest in identifying, lineage tracing, and determining the physiologic roles of monophagocytes in Alzheimer’s disease. While Cx3cr1 knock-in fluorescent reporting and Cre expressing mice have been critical for studying neuroimmunology, mice that are homozygous null or hemizygous for CX3CR1 have perturbed neural development and immune responses. There is, therefore, a need for similar tools in which mice are CX3CR1+/+. Here, we describe a mouse where Cre is driven by the Cx3cr1 promoter on a bacterial artificial chromosome (BAC) transgene (Cx3cr1-CreBT) and the Cx3cr1 locus is unperturbed. Similarly to Cx3cr1-Cre knock-in mice, these mice express Cre in Ly6C-, but not Ly6C+, monocytes and tissue macrophages, including microglia. These mice represent a novel tool that maintains the Cx3cr1 locus while allowing for selective gene targeting in monocytes and tissue macrophages.

The study of immunity in Alzheimer’s requires the ability to identify and quantify specific immune cell subsets by flow cytometry. While it is possible to identify lymphocyte subsets based on cell lineage-specific markers, the lack of such markers in brain myeloid cell subsets has prevented the study of monocytes, macrophages and dendritic cells. By improving on tissue homogenization, we present a comprehensive protocol for flow cytometric analysis, that allows for the identification of several cell types that have not been previously identified by flow cytometry. These cell types include F4/80hi macrophages, which may be meningeal macrophages, IA/IE+ macrophages, which may represent perivascular macrophages, and dendritic cells. The identification of these cell types now allows for their study by flow cytometry in homeostasis and disease.

Group problem-solving skills training for self-harm: randomised controlled trial

Background: Rates of self-harm are high and have recently increased. This trend and the repetitive nature of self-harm pose a significant challenge to mental health services. Aims: To determine the efficacy of a structured group problem-solving skills training (PST) programme as an intervention approach for self-harm in addition to treatment as usual (TAU) as offered by mental health services. Method: A total of 433 participants (aged 18-64 years) were randomly assigned to TAU plus PST or TAU alone. Assessments were carried out at baseline and at 6-week and 6-month follow-up and repeated hospital-treated self-harm was ascertained at 12-month follow-up. Results: The treatment groups did not differ in rates of repeated self-harm at 6-week, 6-month and 12-month follow-up. Both treatment groups showed significant improvements in psychological and social functioning at follow-up. Only one measure (needing and receiving practical help from those closest to them) showed a positive treatment effect at 6-week (P = 0.004) and 6-month (P = 0.01) follow-up. Repetition was not associated with waiting time in the PST group. Conclusions: This brief intervention for self-harm is no more effective than treatment as usual. Further work is required to establish whether a modified, more intensive programme delivered sooner after the index episode would be effective.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

The role of age and emotional valence in word recognition: an ex-Gaussian analysis

The aim of this work is to evaluate the roles of age and emotional valence in word recognition in terms of ex-Gaussian distribution components. In order to do that, a word recognition task was carried out with two age groups, in which emotional valence was manipulated. Older participants did not present a clear trend for reaction times. The younger participants showed significant statistical differences in negative words for target and distracting conditions. Addressing the ex-Gaussian tau parameter, often related to attentional demands in the literature, age-related differences in emotional valence seem not to have an effect for negative words. Focusing on emotional valence for each group, the younger participants only showed an effect on negative distracting words. The older participants showed an effect regarding negative and positive target words, and negative distracting words. This suggests that the attentional demand is higher for emotional words, in particular, for the older participants.

Rôle de la protéine-associée aux microtubules MAP2 dans l'acquisition et le maintien du phénotype neuronal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Promoción de salud y prevención de adicciones en adolescentes mediante la actividad física y el arte : Proyecto Faro

El Proyecto Faro se lleva a cabo a mediante la Cátedra de Teoría de la práctica artística de la Facultad de Bellas Artes y la Cátedra Seminario de actividad física para la salud de la facultad de Humanidades y Ciencias de la Educación de la UNLP. Mediante este proyecto se desarrollaron guías de promoción de salud y prevención de adicciones destinadas a adolescentes para ser utilizadas a nivel escolar y extraescolar. Objetivo: Potenciar la salud con especial énfasis en la prevención de adicciones a través del arte y la actividad física en jóvenes adolescentes, disminuyendo el riesgo de adquirir hábitos no saludables. Metodología: Intervención por medio de talleres con carácter de encuentros sistemáticos en grupos de jóvenes en diferentes ámbitos, utilizando las guías mencionadas. Discusión: Las intervenciones multidisciplinarias que incluyen a la Educación Física y el arte, han demostrado tener gran aceptación por parte de alumnos, docentes y padres, y potencialmente son una estrategia válida para promover salud en estos grupos poblacionales

Promoción de salud y prevención de adicciones en adolescentes mediante la actividad física y el arte : Proyecto Faro

El Proyecto Faro se lleva a cabo a mediante la Cátedra de Teoría de la práctica artística de la Facultad de Bellas Artes y la Cátedra Seminario de actividad física para la salud de la facultad de Humanidades y Ciencias de la Educación de la UNLP. Mediante este proyecto se desarrollaron guías de promoción de salud y prevención de adicciones destinadas a adolescentes para ser utilizadas a nivel escolar y extraescolar. Objetivo: Potenciar la salud con especial énfasis en la prevención de adicciones a través del arte y la actividad física en jóvenes adolescentes, disminuyendo el riesgo de adquirir hábitos no saludables. Metodología: Intervención por medio de talleres con carácter de encuentros sistemáticos en grupos de jóvenes en diferentes ámbitos, utilizando las guías mencionadas. Discusión: Las intervenciones multidisciplinarias que incluyen a la Educación Física y el arte, han demostrado tener gran aceptación por parte de alumnos, docentes y padres, y potencialmente son una estrategia válida para promover salud en estos grupos poblacionales

Biogenic opal, biogenic barium, calcium carbonate and U/Th isotope data from core-top sediments of SONNE cruise SO202 (INOPEX)

Sedimentary proxies used to reconstruct marine productivity suffer from variable preservation and are sensitive to factors other than productivity. Therefore, proxy calibration is warranted. Here we map the spatial patterns of two paleoproductivity proxies, biogenic opal and barium fluxes, from a set of core-top sediments recovered in the Subarctic North Pacific. Comparisons of the proxy data with independent estimates of primary and export production, surface water macronutrient concentrations and biological pCO2 drawdown indicate that neither proxy shows a significant correlation with primary or export productivity for the entire region. Biogenic opal fluxes, when corrected for preservation using 230Th-normalized accumulation rates, show a good correlation with primary productivity along the volcanic arcs (tau = 0.71, p = 0.0024) and with export productivity throughout the western Subarctic North Pacific (tau = 0.71, p = 0.0107). Moderate and good correlations of biogenic barium flux with export production (tau = 0.57, p = 0.0022) and with surface water silicate concentrations (tau = 0.70, p = 0.0002) are observed for the central and eastern Subarctic North Pacific. For reasons unknown, however, no correlation is found in the western Subarctic North Pacific between biogenic barium flux and the reference data. Nonetheless, we show that barite saturation, uncertainty in the lithogenic barium corrections and problems with the reference datasets are not responsible for the lack of a significant correlation between biogenic barium flux and the reference data. Further studies evaluating the factors controlling the variability of the biogenic constituents in the sediments are desirable in this region.

Population and Government in Colonial Buenos Aires. An Approach to the Study of the Tensions Generated by Demographic Growth in the City (1740-1776)

The relationship between population and government in the City of Buenos Aires is analyzed, focusing on the tensions generated by the arrival of new individuals, a local elite with great interests in commerce and in charge of community affairs, and Spanish functionaries that progressively adopted the ideals of the Bourbon Dynasty, despite also being implicated in local logics. It interests us to observe the governors’ perspectives with respect to everyday developments in the city, their preoccupations and interests, and how they would vary the mechanisms to which they resorted in order to organize daily life, in the period defined between 1740 and 1776.

Expresiones no verbales como enunciados realizativos: construcciones preposicionales y apelaciones enfáticas

El presente estudio revisa la caracterización de los enunciados realizativos, deteniéndose en aquellos que no presentan estructura oracional. Así, analizaremos las expresiones no verbales que presentan las características propiamente performativas: construcciones preposicionales encabezadas por núcleos ´locativos`, ´sumativos` y ´sustractivos` y apelaciones enfáticas. En este sentido, podremos determinar el valor de las preposiciones que introducen sintagmas equivalentes a predicados con sentido realizativo. Por otro lado, distinguiremos dos modos de enunciar en relación con la descortesía y la adulación: insultos y halagos. Dichas expresiones se describirán desde una perspectiva gramatical y prosódica, de modo que se atenderá a su capacidad para reproducir enunciados realizativos convencionales y de orientar el acento y la inflexión melódica a la transformación cognitiva y emocional de la realidad del individuo receptor.

Líneas posibles de avance del modelo de Sraffa

Diversas consideraciones históricas e ideológicas han impedido la difusión de la obra fundamental de Sraffa Producción de mercancías por medio de mercancías. La obra de Sraffa ha sido estudiada fundamentalmente en sus aspectos matemáticos por economistas tales como Garegnani, Abraham-Frois, Pasinetti, Steedman, Kurz, Roncaglia, etc. pero sin desarrollar apenas sus aspectos teóricos y económicos. En este artículo se hacen algunas consideraciones sobre posibles desarrollos del libro de Sraffa a partir de su propio esquema de pensamiento.

Promoción de salud y prevención de adicciones en adolescentes mediante la actividad física y el arte : Proyecto Faro

El Proyecto Faro se lleva a cabo a mediante la Cátedra de Teoría de la práctica artística de la Facultad de Bellas Artes y la Cátedra Seminario de actividad física para la salud de la facultad de Humanidades y Ciencias de la Educación de la UNLP. Mediante este proyecto se desarrollaron guías de promoción de salud y prevención de adicciones destinadas a adolescentes para ser utilizadas a nivel escolar y extraescolar. Objetivo: Potenciar la salud con especial énfasis en la prevención de adicciones a través del arte y la actividad física en jóvenes adolescentes, disminuyendo el riesgo de adquirir hábitos no saludables. Metodología: Intervención por medio de talleres con carácter de encuentros sistemáticos en grupos de jóvenes en diferentes ámbitos, utilizando las guías mencionadas. Discusión: Las intervenciones multidisciplinarias que incluyen a la Educación Física y el arte, han demostrado tener gran aceptación por parte de alumnos, docentes y padres, y potencialmente son una estrategia válida para promover salud en estos grupos poblacionales

Implication du domaine intracellulaire du précurseur de la protéine amyloïde dans la modulation de la plasticité synaptique

Alzheimer's disease is the most common type of dementia in the elderly; it is characterized by early deficits in learning and memory formation and ultimately leads to a generalised loss of higher cognitive functions. While amyloid beta (Aβ) and tau are traditionally associated with the development of Alzheimer disease, recent studies suggest that other factors, like the intracellular domain (APP-ICD) of the amyloid precursor protein (APP), could play a role. In this study, we investigated whether APP-ICD could affect synaptic transmission and synaptic plasticity in the hippocampus, which is involved in learning and memory processes. Our results indicated that overexpression of APP-ICD in hippocampal CA1 neurons leads to a decrease in evoked AMPA-receptor and NMDA-receptor dependent synaptic transmission. Our study demonstrated that this effect is specific for APP-ICD since its closest homologue APLP2-ICD did not reproduce this effect. In addition, APP-ICD blocks the induction of long term potentiation (LTP) and leads to increased of expression and facilitated induction of long term depression (LTD), while APLP2-ICD shows neither of these effects. Our study showed that this difference observed in synaptic transmission and plasticity between the two intracellular domains resides in the difference of one alanine in the APP-ICD versus a proline in the APLP2-ICD. Exchanging this critical amino-acid through point-mutation, we observed that APP(PAV)-ICD had no longer an effect on synaptic plasticity. We also demonstrated that APLP2(AAV)-ICD mimic the effect of APP-ICD in regards of facilitated LTD. Next we showed that the full length APP-APLP2-APP (APP with a substitution of the Aβ component for its homologous APLP2 part) had no effect on synaptic transmission or synaptic plasticity when compared to the APP-ICD. However, by activating caspase cleavage prior to induction of LTD or LTP, we observed an LTD facilitation and a block of LTP with APP-APLP2-APP, effects that were not seen with the full length APLP2 protein. APP is phosphorylated at threonine 668 (Thr668), which is localized directly after the aforementioned critical alanine and the caspase cleavage site in APP-APLP2-APP. Mutating this Thr668 for an alanine abolishes the effects on LTD and restores LTP induction. Finally, we showed that the facilitation of LTD with APP-APLP2-APP involves ryanodine receptor dependent calcium release from intracellular stores. Taken together, we propose the emergence of a new APP intracellular domain, which plays a critical role in the regulation of synaptic plasticity and by extension, could play a role in the development of memory loss in Alzheimer’s disease.