Stress is well-known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognized in the development of neurodegenerative disorders, such as Alzheimer's disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3, and 21 days) were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occluding, and glucose transporter-1) and astroglia (GFAP). Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, 1-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5, and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes, cognitive and behavioral dysfunctions.
Rotifers have been used in biological research as well-characterized models of aging. Their multi-organ characters and their sensitivity for chemicals and environmental changes make them useful as in vivo toxicological and lifespan models. Our aim was to create a bdelloid rotifer model to use in high-throughput viability and non-invasive assays. In order to identify our species Philodina acuticornis odiosa (PA), 18S rDNA-based phylogenetic analysis was carried out and their species-specific morphological markers identified. To execute the rotifer-based experiments, we developed an oil-covered water-drop methodology adapted from human in vitro fertilization techniques. This enables toxicological observations of individual one-housed rotifers in a closed and controllable micro-environment for up to several weeks. Hydrogen peroxide (HO) and sodium azide (NaN) exposures were used as well-understood toxins. The toxicity and survival lifespan (TSL), the bright light disturbance (BLD) the mastax contraction frequency (MCF) and the cellular reduction capacity (CRC), indices were recorded. These newly developed assays were used to test the effects of lethal and sublethal doses of the toxins. The results showed the expected dose-dependent decrease in indices. These four different assays can either be used independently or as an integrated system for studying rotifers. These new indices render the PA invertebrate rotifer model a quantitative system for measuring viability, toxicity and lifespan (with TSL), systemic reaction capacity (with BLD), organic functionality (with MCF) and reductive capability of rotifers (with CRC), in vivo. This novel multi-level system is a reliable, sensitive and replicable screening tool with potential application in pharmaceutical science.
Clinical diagnosis of Alzheimer's disease (AD) relying on symptomatic features has a low specificity, emphasizing the importance of the pragmatic use of neurochemical biomarkers. The most advanced and reliable markers are amyloid-β (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) with relatively high levels of sensitivity, specificity, and diagnostic accuracy. Recent advances within the field of proteomics offer the potential to search for novel biomarkers in CSF by using modern methods, such as microarrays. The purpose of this study was to identify pathognostic proteins in CSF obtained from patients whose clinical AD diagnosis was confirmed by the "core" biomarkers. CSF samples were obtained from 25 AD patients and 25 control individuals. The levels of Aβ42, t-tau, and p-tau were measured by ELISA. In the microarray experiments, ultrasensitive slides representing of 653 antigens were used. Apolipoprotein E genotyping was also determined. A decrease of seven CSF proteins in AD were found, four of them (POLG, MGMT, parkin, and ApoD) have a protective function against neuronal death, while the remaining three proteins (PAR-4, granzyme B, Cdk5) trigger multiple pathways facilitating neuronal cell death. Since these proteins from CSF samples could not be identified by western blot, their decreased levels in AD patients were not verified. Our results provide new information of pathognostic importance of POLG and granzyme B in AD. Although the function of MGMT, parkin, ApoD, PAR-4, and Cdk5 was previously known in AD, the findings presented here provide novel evidence of the significance of CSF analysis in the mapping of the AD pathomechanism.
Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of antidepressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated proinflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients.
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