Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease.

Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity

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The present study investigates the influence of fatigue load on the stress-strain behavior of balanced angular laminates. The nonlinear behavior is described by an elastic-viscoplastic material model. The model parameters are determined, and the model behavior is used to draw conclusions to the micromechanical supporting behavior of the materials under investigation. A loading and measurement system was developed to carry out the experiments. This system exposes fiber composite specimens to loads with a preselectable deformation profile and analyses the stress-strain curves of the specimens under investigation. By appropriately selecting the electrical and mechanical components, and using a computer program for control, measurement and analysis, adapted to the same, it is possible to make a very exact determination of the time relation of strain and stress, which is of significance to this study. Owing to the almost identical setup of the measurement facilities for stress and strain, errors in the measurement of the phase position of both parameters were minimized. In specified load cycle number intervals during fatigue loading, the rheologic behavior of the specimens under investigation was registered under load via four strain amplitudes and three-and-a-half frequency decades. (orig.)Available from TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman