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A clinical/immunological neuromyelitis optica association studyKitley, Joanna Louise January 2014 (has links)
Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are associated with the disease-specific autoantibody aquaporin-4 (AQP4-Ab), which is thought to be pathogenic. Some NMO/NMOSD patients do not have this antibody and may have different clinical and immuno-pathological disease characteristics, but previous clinical NMO/NMOSD studies have been confounded by inclusion of such patients. To define better the characteristics of AQP4-Ab disease, disease course, outcomes and predictors of disability were investigated in 106 AQP4-Ab positive NMO/NMOSD patients from the UK and Japan. AQP4-Ab positivity conferred a high risk of relapsing disease and substantial disability; age at disease onset and ethnicity were important predictors of disability type. Visual disability was more common in younger patients and those of Afro-Caribbean ethnicity whilst older patients and Caucasian patients were more at risk of motor disability. To determine whether disease characteristics were influenced by AQP4-Ab binding specificities, the differential binding of patient AQP4-Ab against the two main AQP4 isoforms was investigated. Although the relative binding to the two isoforms differed between patients, there was no association between these differences and clinical features such as relapse type, severity, onset age and ethnicity. The clinical and in vitro characteristics of AQP4-Ab negative NMO/NMOSD patients were studied. It was shown that these patients represent an aetiologically heterogeneous group. Some have other inflammatory and infectious disorders, some have low levels of AQP4-Ab and a significant proportion have antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab). Others have antibodies that bind to neurons or oligodendrocytes in primary cultures. Attempts to identify novel antigens by immunocapture techniques were made, but were not successful. Patients with MOG-Ab showed differences when compared to those with AQP4-Ab including higher proportion of males, younger age at disease onset and greater likelihood of conus involvement on imaging. Additionally, patients with MOG-Ab appear to have more favourable outcomes, with better improvement from the onset attack and a lower probability of subsequent relapses. In conclusion, the work in this thesis has shown that AQP4-Ab disease is not synonymous with the term NMO and that seronegative NMO/NMOSD patients represent a clinically and aetiologically heterogeneous group and should therefore be classed separately from those with AQP4-Ab.
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Histopathological assessment of atroglial aquaporin-4 expression in chronic traumatic encephalopathyBabcock, Katharine Jane 03 July 2018 (has links)
BACKGROUND: The accumulation of misfolded proteins is a hallmark of many neurodegenerative disorders, including Chronic Traumatic Encephalopathy (CTE). Intracellular protein degradation pathways appear to be insufficient in preventing or halting disease progression. A brain-wide waste clearance pathway mediated by astroglial aquaporin-4 (AQP4) water channels in the perivascular space called the “glymphatic system” has recently been identified. Disruption of this system due to mislocalization of AQP4 away from perivascular astrocytic endfeet (“depolarization”) is linked to reductions in solute clearance and the build up of toxic metabolites in different neurologic conditions associated with aging and traumatic brain injury. Accumulation of aggregated tau protein around blood vessels at the depths of cortical sulci is considered the pathognomonic lesion of CTE, and may reflect impairment of glymphatic pathway function in these perivascular spaces.
OBJECTIVES: To investigate whether changes in AQP4 expression or perivascular AQP4 polarization are present in CTE and to assess their relationship with CTE lesions. Additionally, AQP4 expression in CTE will be compared to subjects with a pathological diagnosis of Alzheimer’s disease (AD) and non-pathological controls without a history of head trauma.
METHODS: Postmortem frontal cortex samples from neuropatholigcally confirmed cases of CTE, AD, and non-pathological controls were provided by the VA-BU-CLF Brain Bank. Fixed tissue samples were cut at 20 microns from each case and immunofluorescently stained for AQP4, glial fibrillary acidic protein (GFAP), and phosphorylated tau (AT-8). Slides were imaged using a Zeiss 880 Airyscan confocal microscope and analyzed using the HALO image software analysis platform. RESULTS: Increased perivascular AQP4 polarization was significantly associated with lesional vessels compared to non-lesional vessels in CTE (p=0.0187). When assessed between groups, CTE showed less AQP4 polarization surrounding non-lesional vessels compared to controls, and seemingly higher polarization around lesional vessels compared to AD, however these differences were not statistically significant. CONCLUSIONS: Blood brain barrier (BBB) breakdown is a common occurrence following traumatic brain injury (TBI) and has previously been confirmed in postmortem cases of CTE. The findings reported in the current study showing increased, rather than decreased, perivascular AQP4 polarization around lesional vessels compared to non-lesional vessels in CTE may therefore reflect a compensatory mechanism of astrocytes in response to secondary vasogenic edema in the face of chronic inflammation and disrupted BBB integrity, rather than acute cytotoxic edema which is likely the main driver of AQP4 depolarization reported in previous studies.
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Studies on aquaporin 4, a molecular determinant of brain water homeostasis /Gunnarson, Eli, January 2006 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.
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Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult miceMorrison, Helena W., Filosa, Jessica A. 12 1900 (has links)
Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. In this study we assessed astrocyte Ca2+ dynamics, aquaporin 4 (AQP4) polarity, Sloop expression pattern, as well as, microglia morphology and phagocytic marker CD11b in male and female mice following 60 min of middle cerebral artery (MCA) occlusion. We reveal sex differences in the frequency of intracellular astrocyte Ca2+ elevations (F-(1,F-86) = 8.19, P = 0.005) and microglia volume (F-(1,F-40) = 12.47, P = 0.009) immediately following MCA occlusion in acute brain slices. Measured in fixed tissue, AQP4 polarity was disrupted (F-(5,F-86) = 3.30, P = 0.009) and the area of non-S100 beta immunoreactivity increased in ipsilateral brain regions after 60 min of MCA occlusion (F-(5,F-86) = 4.72, P = 0.007). However, astrocyte changes were robust in male mice when compared to females. Additional sex differences were discovered regarding microglia phagocytic receptor CD11b. In sham mice, constitutively high CD11b immunofluorescence was observed in females when compared to males (P = 0.03). When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P = 0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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Aquaporin 4 promotes Drug Tolerance to AMG 510 in KRASG12C mutant Non-Small Cell Lung CancerLuna, Nastassja G 01 January 2024 (has links) (PDF)
Lung cancer is the leading cause of cancer-related deaths worldwide. One of the most common genetic aberrations in lung cancer patients is Kirsten rat sarcoma viral oncogene homolog (KRAS). The KRAS protein is a Ras superfamily GTPase that switches between an active GTP-bound form and an inactive GDP-bound form. The consequence of KRAS mutations results in constitutively active downstream pathways involved in uncontrolled cell proliferation and survival. Fortunately, there has been a recent development of KRASG12C inhibitors that directly target mutant KRAS, thereby arresting its proliferative effects. A recently FDA-approved KRASG12C inhibitor for the treatment of non-small cell lung cancer, Sotorasib (AMG 510), has been shown to produce insubstantial clinical response rates and a short duration of response. Similar to other targeted therapies, the limitations of this treatment are primarily due to the emergence of drug resistance. Drug resistance has been studied extensively regarding other anticancer treatments; however, the underlying molecular mechanisms remain poorly characterized. Our investigation begins by establishing and analyzing a subpopulation of cancer cells that evolve and mediate drug resistance, known as drug-tolerant persister cells (DTPCs), in KRASG12C mutant cells using AMG 510. First, we observed the reactivation of a pro-proliferative kinase, ERK, in AMG 510 DTPCs. Additionally, whole transcriptomics analysis, RT-qPCR, and immunofluorescent staining demonstrated significant upregulation of AQP4 in AMG 510 DTPCs compared to drug sensitive cells (DSCs). Aquaporin 4 (AQP4) is a water-selective transmembrane protein that regulates fluid homeostasis in many organ systems, including the lungs, and is involved in intracellular calcium signaling. We aim to explore the connections between AQP4, ERK, and calcium signaling in promoting drug tolerance to AMG 510. The insights gained from this research could lead to improved targeted therapies and clinical outcomes by identifying AQP4 as a resistance-driving biomarker.
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The role of aquaporin-4 in subarachnoid haemorrhageTait, Matthew James January 2011 (has links)
Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.
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Effect of water deprivation on aquaporin 4 (AQP4) mRNA expression in chickens (Gallus domesticus)SAITO, Noboru, IKEGAMI, Hidehiro, SHIMADA, Kiyoshi 11 1900 (has links)
No description available.
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Caractérisation de la réponse immune dans la neuromyelite optique / Characterization of the immune response in neuromyelitis opticaChanson, Jean-Baptiste 19 September 2013 (has links)
La neuromyélite optique (NMO) est une maladie inflammatoire du système nerveux central récemment mieux comprise par la découverte d’un anticorps sérique spécifique dirigé contre l’aquaporine 4 (anticorps anti-AQP4). L’objectif de cette thèse a été de développer une recherche translationnelle pour améliorer la connaissance de la réponse immunitaire dans la NMO. Nous avons d’abord développé et étudié un modèle animal de NMO en laboratoire afin de mieux comprendre la physiopathologie d’une inflammation optico-médullaire. Nous avons aussi amélioré la connaissance de la NMO humaine. Nous avons montré que la réactivité anti-AQP4 n’était pas corrélée à l’activité de la maladie et retrouvé une réactivité contre d’autres protéines que l’AQP4. Nous avons aussi mis en évidence des anomalies métaboliques sériques (scyllo-inositol et acétate), et une diminution du volume de la substance blanche cérébrale, ce qui ouvre la voie à de nouvelles recherches pour confirmer et exploiter ces résultats. / Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system in which a specific antibody targeting aquaporin 4 (anti-AQP4) was recently found. The aim of this thesis is to develop a translational research in order to improve our knowledge of the immune response in NMO. We have therefore studied a animal model mimicking NMO and allowing a better comprehension of optico-spinal inflammation. In the human subjects suffering from NMO, we have also found that anti-AQP4 reactivity was not correlated to the disease activity and that reactivities against other proteins may exist. We have discovered changes in the serum concentrations of some metabolites (scyllo-inositol and acetate) and a decrease in the volume of brain white matter. These findings have to be confirmed by other studies and may improve our comprehension of NMO.
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Úloha Aquaporin 4 kanálů a Transient Receptor Potential Vanilloid 4 kanálů při objemových změnách astrocytů / The Role of Aquaporin 4 channels and Transient Receptor Potential Vanilloid 4 channels in astrocytic swellingHeřmanová, Zuzana January 2019 (has links)
Astrocytes posses a wide range of functions within the brain. In response to ischemic conditions they swell due to increased uptake of osmolytes and they are mainly responsible for cytotoxic edema formation. However, they are also able to regulate their volume by releasing osmolytes together with water via the process of regulatory volume decrease (RVD). The Aquaporin 4 (AQP4) channel and Transient receptor potential vanilloid 4 (TRPV4) channel are suspected to be strongly involved in these processes of astrocytic volume regulation. The goal of the present diploma thesis was to clarify the role of both channels in astrocytic swelling in situ. For our experiments we used a subpopulation of green fluorescent protein-labelled astrocytes from AQP4-deficient (AQP4-/- ), TRPV4-deficient (TRPV4-/- ) and control (Ctrl) mice. Cell volume alterations were induced in acute brain slices by hypoosmotic stress or by oxygen-glucose deprivation (OGD). Data were quantified using fluorescence intensity-based approach in the whole cells and in astrocytic endfeet. Our results indicate, that there is no difference in astrocytic swelling or cell volume recovery between astrocytes from AQP4-/- , TRPV4-/- and control mice when exposed to hypoosmotic stress. On the contrary, volume changes induced by OGD varied...
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AQUAPORIN 4 EXPRESSION AND DISTRIBUTION DURING OSMOTIC BRAIN EDEMA AND FOLLOWING CHRONIC TREATMENT OF DESIPRAMINERobinson, Sergei Alexander 24 August 2011 (has links)
No description available.
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