Hydrocephalus induces dynamic spatiotemporal regulation of aquaporin-4 expression in the rat brain

<p>Abstract</p> <p>Background</p> <p>The water channel protein aquaporin-4 (AQP4) is reported to be of possible major importance for accessory cerebrospinal fluid (CSF) circulation pathways. We hypothesized that changes in AQP4 expression in specific brain regions correspond to the severity and duration of hydrocephalus.</p> <p>Methods</p> <p>Hydrocephalus was induced in adult rats (~8 weeks) by intracisternal kaolin injection and evaluated after two days, one week and two weeks. Using magnetic resonance imaging (MRI) we quantified lateral ventricular volume, water diffusion and blood-brain barrier properties in hydrocephalic and control animals. The brains were analysed for AQP4 density by western blotting and localisation by immunohistochemistry. Double fluorescence labelling was used to study cell specific origin of AQP4.</p> <p>Results</p> <p>Lateral ventricular volume was significantly increased over control at all time points after induction and the periventricular apparent diffusion coefficient (ADC) value significantly increased after one and two weeks of hydrocephalus. Relative AQP4 density was significantly decreased in both cortex and periventricular region after two days and normalized after one week. After two weeks, periventricular AQP4 expression was significantly increased. Relative periventricular AQP4 density was significantly correlated to lateral ventricular volume. AQP4 immunohistochemical analysis demonstrated the morphological expression pattern of AQP4 in hydrocephalus in astrocytes and ventricular ependyma. AQP4 co-localized with astrocytic glial fibrillary acidic protein (GFAP) in glia limitans. In vascular structures, AQP4 co-localized to astroglia but not to microglia or endothelial cells.</p> <p>Conclusions</p> <p>AQP4 levels are significantly altered in a time and region dependent manner in kaolin-induced hydrocephalus. The presented data suggest that AQP4 could play an important neurodefensive role, and may be a promising future pharmaceutical target in hydrocephalus and CSF disorders.</p

Blood-brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: Protective effect by estradiol treatment in ovariectomized animals

Strong evidence involves aquaporin-4 (AQP4) in the physiopathology of brain edema. Two major points remain unsolved: (1) the capacity of perivascular glial cells to regulate AQP4 in response to disruption of the blood-brain barrier (BBB); and (2) the potential beneficial role of AQP4 in the clearance of brain edema. We used intraparenchymal injection of lipopolysaccharide (LPS) as an efficient model to induce BBB disruption. This was monitored by IgG extravasation and AQP4 was studied at the mRNA and protein level. The first signs of BBB disruption coincided with strong induction of AQP4 mRNA in perivascular glial cells. At the early phase, estradiol treatment highly prevented the LPS-induced disruption of the BBB and the induction of AQP4. Efficient clearance of vasogenic edema is supposed to occur once BBB is restored. This phase coincided with high induction of AQP4 mRNA in parenchymal reactive astrocytes and perivascular glial processes. High levels of AQP4 mRNA may be beneficial under these conditions. Our data may clarify why estradiol treatment reduces mortality in conditions typically associated with edema formation, like stroke.Peer Reviewe

Blood-brain barrier disruption highly induces aquaporin-4 mRNA and protein in perivascular and parenchymal astrocytes: Protective effect by estradiol treatment in ovariectomized animals

Strong evidence involves aquaporin-4 (AQP4) in the physiopathology of brain edema. Two major points remain unsolved: (1) the capacity of perivascular glial cells to regulate AQP4 in response to disruption of the blood-brain barrier (BBB); and (2) the potential beneficial role of AQP4 in the clearance of brain edema. We used intraparenchymal injection of lipopolysaccharide (LPS) as an efficient model to induce BBB disruption. This was monitored by IgG extravasation and AQP4 was studied at the mRNA and protein level. The first signs of BBB disruption coincided with strong induction of AQP4 mRNA in perivascular glial cells. At the early phase, estradiol treatment highly prevented the LPS-induced disruption of the BBB and the induction of AQP4. Efficient clearance of vasogenic edema is supposed to occur once BBB is restored. This phase coincided with high induction of AQP4 mRNA in parenchymal reactive astrocytes and perivascular glial processes. High levels of AQP4 mRNA may be beneficial under these conditions. Our data may clarify why estradiol treatment reduces mortality in conditions typically associated with edema formation, like stroke.Peer Reviewe

Vacuolar degeneration affecting brain acrophages/microglia in variant CJD: a report on two cases

We present the neuropathology of two cases of variant Creutzfeldt-Jakob disease (vCJD) showing significant vacuolar degenerative alterations specifically affecting brain macrophages/microglia within the thalamus and, to a lesser extent, within the neocortical grey matter. Vacuolar degeneration in these cells was extensive, and likely to be associated with the development of a uniform sub-type of ‘spongiform’ vacuole seen in vCJD. The extensive morphological alterations described here closely resemble those very recently reported by Zucconi and colleagues, in response to experimental copper deficiency induced through dietary restriction, but could not be detected in cases of sporadic CJD examined. The significance of these novel findings are discussed in relation to copper homeostasis, loss of function of cellular prion protein and aberrant lysosomal catabolism within brain macrophages/microglia. This type of vacuolation may constitute a component of the overall profile of spongiform changes associated with vCJD

Up-regulation of microglial cathepsin C expression and activity in lipopolysaccharide-induced neuroinflammation

<p>Abstract</p> <p>Background</p> <p>Cathepsin C (Cat C) functions as a central coordinator for activation of many serine proteases in inflammatory cells. It has been recognized that Cat C is responsible for neutrophil recruitment and production of chemokines and cytokines in many inflammatory diseases. However, Cat C expression and its functional role in the brain under normal conditions or in neuroinflammatory processes remain unclear. Our previous study showed that Cat C promoted the progress of brain demyelination in cuprizone-treated mice. The present study further investigated the Cat C expression and activity in lipopolysaccharide (LPS)-induced neuroinflammation <it>in vivo</it> and <it>in vitro.</it></p> <p>Methods</p> <p>C57BL/6 J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and <it>in situ</it> hybridization (ISH) were used to analyze microglial activation, TNF-α, IL-1β, IL-6, iNOS mRNAs expressions and cellular localization of Cat C in the brain. Nitrite assay was used to examine microglial activation <it>in vitro</it>; RT-PCR and ELISA were used to determine the expression and release of Cat C. Cat C activity was analyzed by cellular Cat C assay kit. Data were evaluated for statistical significance with paired <it>t</it> test.</p> <p>Results</p> <p>Cat C was predominantly expressed in hippocampal CA2 neurons in C57BL/6 J mice under normal conditions. Six hours after LPS injection, Cat C expression was detected in cerebral cortical neurons; whereas, twenty-four hours later, Cat C expression was captured in activated microglial cells throughout the entire brain. The duration of induced Cat C expression in neurons and in microglial cells was ten days and three days, respectively. <it>In vitro</it>, LPS, IL-1β and IL-6 treatments increased microglial Cat C expression in a dose-dependent manner and upregulated Cat C secretion and its activity.</p> <p>Conclusions</p> <p>Taken together, these data indicate that LPS and proinflammatory cytokines IL-1β, IL-6 induce the expression, release and upregulate enzymatic activity of Cat C in microglial cells. Further investigation is required to determine the functional role of Cat C in the progression of neuroinflammation, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.</p