Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant’s demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH.This research was funded by grants PI16/00493 and PI19/01096 to M.E. from the Spanish Ministry of Economy and Competitiveness, co-financed by the Carlos III Health Institute (ISCIII) and European Regional Development Fund (FEDER). J.L.T-C. was partially supported by the Regional Government of Andalusia and FEDER funds through a program for recruitment of young researchers

Conservation status and limiting factors in the endangered population of Egyptian vulture (Neophron percnopterus) in the Canary Islands

Egyptian vulture populations have decreased sharply in the Western Palearctic; island populations are almost extinct in the Mediterranean and the Macaronesian regions. In the Canary archipelago, the species only survives in the islands of Fuerteventura and Lanzarote. During 1998-2001 we examined population parameters and evaluated some potential limiting factors for this isolated and sedentary population. The total population (breeding and non-breeding birds) was monitored annually. In addition, 26 fledglings and 33 immatures (6 years old birds) and immature annual survival rates were similar, around 90%. Adult survival was lower than expected as territorial birds seem more susceptible to poisoning. Immature survival could be favoured by the existence of regular feeding places. Casualties from power lines was the main cause of mortality (12 cases during the study period). Blood sampling revealed high frequencies of lead poisoning: 13.5 and 2.7% of individuals showed sub-clinical and clinical intoxication levels, respectively, probably caused by the ingestion of lead shot. Priority conservation measures should be directed to reduce electrocution risks, illegal poisoning, and lead contamination. Population reinforcement with birds coming from other populations is not recommended as previous information reveals morphological and genetic differentiation of Canarian Egyptian vultures compared with continental populations. © 2002 Elsevier Science Ltd. All rights reserved.Peer Reviewe

Aquaporin-4 Expression Switches from White to Gray Matter Regions during Postnatal Development of the Central Nervous System

Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system and plays a fundamental role in maintaining water homeostasis there. In adult mice, AQP4 is located mainly in ependymal cells, in the endfeet of perivascular astrocytes, and in the glia limitans. Meanwhile, its expression, location, and function throughout postnatal development remain largely unknown. Here, the expression of AQP4 mRNA was studied by in situ hybridization and RT-qPCR, and the localization and amount of protein was studied by immunofluorescence and western blotting, both in the brain and spinal cord. For this, wild-type mice of the C57BL/6 line, aged 1, 3, 7, 11, 20, and 60 days, and 18 months were used. The results showed a change in both the expression and location of AQP4 in postnatal development compared to those during adult life. In the early stages of postnatal development it appears in highly myelinated areas, such as the corpus callosum or cerebellum, and as the animal grows, it disappears from these areas, passing through the cortical regions of the forebrain and concentrating around the blood vessels. These findings suggest an unprecedented possible role for AQP4 in the early cell differentiation process, during the first days of life in the newborn animal, which will lead to myelination

Aquaporin-4 Expression Switches from White to Gray Matter Regions during Postnatal Development of the Central Nervous System

Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system and plays a fundamental role in maintaining water homeostasis there. In adult mice, AQP4 is located mainly in ependymal cells, in the endfeet of perivascular astrocytes, and in the glia limitans. Meanwhile, its expression, location, and function throughout postnatal development remain largely unknown. Here, the expression of AQP4 mRNA was studied by in situ hybridization and RT-qPCR, and the localization and amount of protein was studied by immunofluorescence and western blotting, both in the brain and spinal cord. For this, wild-type mice of the C57BL/6 line, aged 1, 3, 7, 11, 20, and 60 days, and 18 months were used. The results showed a change in both the expression and location of AQP4 in postnatal development compared to those during adult life. In the early stages of postnatal development it appears in highly myelinated areas, such as the corpus callosum or cerebellum, and as the animal grows, it disappears from these areas, passing through the cortical regions of the forebrain and concentrating around the blood vessels. These findings suggest an unprecedented possible role for AQP4 in the early cell differentiation process, during the first days of life in the newborn animal, which will lead to myelination.This study was supported by grant PI19/01096 from the Spanish Ministry of Economy and Competitiveness, co-financed by the Carlos III Health Institute (ISCIII) and European Regional Development Fund (FEDER), and by grant P20_00646 from Regional Department of Economy, Knowledge, Business and University, Junta de Andalucía, Andalusian Plan for Research (PAIDI-2020), both grants awarded to M.E. F.M was supported by an FPU grant from the Spanish Ministry of Universities (FPU17/04825).Peer reviewe

Inhibition of glutamine utilization induces apoptosis by GCN2-dependent activation of a TRAIL-R2/FADD/Caspase-8 pathway in glutamine-addicted tumor cells

Trabajo presentado en el II CABIMER International Workshop. Trends in Cancer Biology and Advanced Therapies, celebrado en Sevilla (España), del 23 al 25 de febrero de 2022Oncogenic transformation triggers reprogramming of metabolism, as part of the tumorigenic process. However, metabolic reprogramming may also increase the sensitivity of transformed cells to microenvironmental stress. We have recently shown that transformation of human breast epithelial cells by the p95HER2 oncogene, markedly sensitizes these cells to metabolic stress induced by simultaneous inhibition of glucose and glutamine metabolism. In p95HER2/611CTF-transformed cells, metabolic stress activates a TRAIL-R2 and caspase-8-dependent apoptotic process that requires prior down-regulation of cellular FLICE-like inhibitor protein (c-FLIP) levels. We further investigated the apoptotic mechanism activated in glutamine-addicted tumor cells in response to glutamine starvation. Glutamine limitation triggers a caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the proapoptotic receptor TRAIL-R2 but is independent of TRAIL. In glutamine-depleted tumor cells, activation of the GCN2/ATF4/CHOP pathway is responsible for the transcriptional up-regulation of TRAIL-R2, caspase-8 activation and apoptotic cell death. Interestingly, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids. In addition, glutamine deprivation induces GCN2-independent FLIP down-regulation facilitating caspase-8 activation and apoptosis. Collectively, our findings uncover a mechanism of apoptosis activation in tumor cells subject to glutamine shortage that could play a key role in the control of tumor initiation and progression by microenvironmental cues

Combined effects of aquaporin-4 and hypoxia produce age-related hydrocephalus.

Aquaporin-4, present in ependymal cells, in glia limiting and abundantly in pericapillary astrocyte foot processes, and aquaporin-1, expressed in choroid plexus epithelial cells, play an important role in cerebrospinal fluid production and may be involved in the pathophysiology of age-dependent hydrocephalus. The finding that brain aquaporins expression is regulated by low oxygen tension led us to investigate how hypoxia and elevated levels of cerebral aquaporins may result in an increase in cerebrospinal fluid production that could be associated with a hydrocephalic condition. Here we have explored, in young and aged mice exposed to hypoxia, whether aquaporin-4 and aquaporin-1 participate in the development of age-related hydrocephalus. Choroid plexus, striatum, cortex and ependymal tissue were analyzed separately both for mRNA and protein levels of aquaporins. Furthermore, parameters such as total ventricular volume, intraventricular pressure, cerebrospinal fluid outflow rate, ventricular compliance and cognitive function were studied in wild type, aquaporin-1 and aquaporin-4 knock-out animals subjected to hypoxia or normoxia. Our data demonstrate that hypoxia is involved in the development of age-related hydrocephalus by a process that depends on aquaporin-4 channels as a main route for cerebrospinal fluid movement. Significant increases in aquaporin-4 expression that occur over the course of animal aging, together with a reduced cerebrospinal fluid outflow rate and ventricular compliance, contribute to produce more severe hydrocephalus related to hypoxic events in aged mice, with a notable impairment in cognitive function. These results indicate that physiological events and/or pathological conditions presenting with cerebral hypoxia/ischemia contribute to the development of chronic adult hydrocephalus