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Lobraico D, Abbrescia P, Fioriello MG, Barile B, Palazzo C, Valente O, Nicchia GP, Dibattista M, Frigeri A. The Aquaporin-4 Expression and Localization in the Olfactory Epithelium Modulate the Odorant-Evoked Responses and Olfactory-Driven Behavior. Glia 2025. [PMID: 40251831 DOI: 10.1002/glia.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/21/2025]
Abstract
Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system (CNS). It serves as the primary water channel in the neuropil and plays roles in physiological functions, including regulating water homeostasis by adjusting cell volume and modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Notably, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Therefore, we aim to uncover the physiological role of AQP4 isoforms, particularly the AQP4ex isoforms (AQP4M1ex, AQP4M23ex) and the orthogonal array of particles (OAPs)-forming isoform (AQP4M23) in the OE. We investigated the impact of AQP4 isoforms on the OE, observing a reduced number of mature olfactory sensory neurons (OSNs), SUSs, and globose basal cells (GBCs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). This suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving cell density. Next, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, where we found reduced odorant responses in mice lacking AQP4 isoforms. Assessments of olfactory ability revealed deficits in odor-guided food-seeking behavior in both AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice exhibited a diminished ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, influencing odorant-evoked responses and cell density in the OE, with AQP4ex emerging as a key regulator despite its low abundance.
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Affiliation(s)
- Donatella Lobraico
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Pasqua Abbrescia
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Maria Grazia Fioriello
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Claudia Palazzo
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Onofrio Valente
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Michele Dibattista
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Antonio Frigeri
- Department of Translational Biomedicine and Neuroscience (DiBraiN), School of Medicine, University of Bari Aldo Moro, Bari, Italy
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Kawiková I, Špička V, Lai JCK, Askenase PW, Wen L, Kejík Z, Jakubek M, Valeš K, Španiel F. Extracellular vesicles as precision therapeutics for psychiatric conditions: targeting interactions among neuronal, glial, and immune networks. Front Immunol 2025; 16:1454306. [PMID: 40264776 PMCID: PMC12011847 DOI: 10.3389/fimmu.2025.1454306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 02/14/2025] [Indexed: 04/24/2025] Open
Abstract
The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.
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Affiliation(s)
- Ivana Kawiková
- National Institute of Mental Health, Klecany, Czechia
- Department of Medicine, Yale School of Medicine, New Haven, CT, United States
- Department of Biology, Hartford University, West Hartford, CT, United States
| | - Václav Špička
- Institute of Physics of the Czech Academy of Sciences, Prague, Czechia
| | - James C. K. Lai
- Department of Biomedical and Pharmaceutical Sciences, Idaho State University College of Pharmacy, Pocatello, ID, United States
- Department of Diagnostic Radiology and Biomedical Imaging, Magnetic Resonance Research Center, Yale School of Medicine, New Haven, CT, United States
| | - Philip W. Askenase
- Department of Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Li Wen
- Department of Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Zdeněk Kejík
- Biotechnology and Biomedical Center in Vestec (BIOCEV) , First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Milan Jakubek
- Biotechnology and Biomedical Center in Vestec (BIOCEV) , First Faculty of Medicine, Charles University, Vestec, Czechia
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Karel Valeš
- National Institute of Mental Health, Klecany, Czechia
- 3rd Medical Faculty, Charles University, Prague, Czechia
| | - Filip Španiel
- National Institute of Mental Health, Klecany, Czechia
- 3rd Medical Faculty, Charles University, Prague, Czechia
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Kawamura K, Kumata K, Yamasaki T, Ogawa M, Kurihara Y, Nengaki N, Nakamura Y, Ono M, Takado Y, Igarashi H, Zhang MR. Efficient one-pot radiosynthesis of the 11C-labeled aquaporin-4 inhibitor TGN-020. EJNMMI Radiopharm Chem 2025; 10:17. [PMID: 40186669 PMCID: PMC11972257 DOI: 10.1186/s41181-025-00338-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND [11C]TGN-020 has been developed as a positron emission tomography (PET) tracer for imaging aquaporin-4 (AQP4) in the brain and used in clinical studies. Previously, [11C]TGN-020 was synthesized through the acylation of [11C]nicotinic acid, produced by the reaction of 3-bromopyridine and n-butyllithium with [11C]CO2, with 2-amino-1,3,4-thiadiazole. In this study, to enhance the automated radiosynthesis efficiency of [11C]TGN-020, we optimized its radiosynthesis procedure using our in-house developed 11C-labeling synthesizer. RESULTS [11C]TGN-020 was synthesized via direct [11C]CO2 fixation using n-butyllithium and 3-bromopyridine in tetrahydrofuran, followed by treatment of lithium [11C]nicotinic acetate with isobutyl chloroformate and subsequent acylation with 2-amino-1,3,4-thiadiazole in the presence of N,N-diisopropylethylamine. The optimized process significantly improved the radiosynthesis efficiency of [11C]TGN-020, achieving a high radiochemical yield based on [11C]CO2 (610‒1700 MBq, 2.8 ± 0.7%) at the end of synthesis (n = 12) and molar activity (Am) of 160-360 GBq/μmol at the end of synthesis (n = 5). The radiosynthesis time and radiochemical purity were approximately 60 min and > 95% (n = 12), respectively. PET studies based on [11C]TGN-020 with different Am values were performed using healthy rats. The radioactive uptake of [11C]TGN-020 with high Am in the cerebral cortex was slightly higher than that with low Am. CONCLUSIONS [11C]TGN-020 with high Am was obtained in reproducible radiochemical yield. Overall, the proposed optimization process for the radiosynthesis of [11C]TGN-020 can facilitate its application as a PET radiopharmaceutical for clinical use.
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Affiliation(s)
- Kazunori Kawamura
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan.
| | - Katsushi Kumata
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
| | - Tomoteru Yamasaki
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
| | - Masanao Ogawa
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
- SHI Accelerator Service Ltd., Tokyo, 141-0032, Japan
| | - Yusuke Kurihara
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
- SHI Accelerator Service Ltd., Tokyo, 141-0032, Japan
| | - Nobuki Nengaki
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
- SHI Accelerator Service Ltd., Tokyo, 141-0032, Japan
| | - Yukimi Nakamura
- Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Maiko Ono
- Quantum Life Spin Group, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
| | - Yuhei Takado
- Quantum Life Spin Group, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
| | - Hironaka Igarashi
- Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), Chiba, 263-8555, Japan
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes in the prefrontal cortex contributes to sex-dependent deficits in cognition and behavior. Mol Psychiatry 2025:10.1038/s41380-025-02993-3. [PMID: 40185903 DOI: 10.1038/s41380-025-02993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with endfeet high in aquaporin-4 (AQP4) expression. These AQP4-rich endfeet facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in neurovascular function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to more pronounced shifts in stress-coping behavior and working memory deficits in male- as compared to female mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased transcripts associated with blood vessel maintenance in males, but either had no effect on- or decreased- these transcripts in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor in males yet has little effect on stress susceptibility in females. Our findings provide evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to cognitive-behavioral consequences following stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Shobha Johnsamuel
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lauren L Vollmer
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alexander M Kuhn
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Eric S Wohleb
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Deng Z, Wang H, Zhong K, Li Y, Deng H, Gao B, Huang K, Tong A, Zhou L. The Role of Choroid Plexus in Hydrocephalus from the Perspective of Structure and Function: a Therapeutic Target. Mol Neurobiol 2025:10.1007/s12035-025-04823-7. [PMID: 40085357 DOI: 10.1007/s12035-025-04823-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/06/2025] [Indexed: 03/16/2025]
Abstract
Hydrocephalus is one of the most common neurological diseases, characterized by abnormal excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. Its pathophysiological mechanism is believed to be related to the imbalance of CSF circulation and homeostasis. As the main source of CSF secretion, the choroid plexus is closely related to hydrocephalus. The choroid plexus is a specialized vascularized tissue located within the cerebral ventricles. It has multiple physiological functions including regulating CSF, immune response, endocrine metabolism, etc. Strategies that reduce choroid plexus CSF secretion have been shown to be effective in the treatment of hydrocephalus. However, the role of other physiological functions of the choroid plexus in hydrocephalus is still unclear. Recent studies on the choroid plexus and the blood-CSF barrier have deepened our understanding of the structure and function of the choroid plexus. The idea of targeting the choroid plexus to treat hydrocephalus has spawned many branches: choroid plexus epithelial cells, choroid plexus immune cells, choroid plexus peptides, and choroid plexus cilia, etc. This review introduces the basic structure and function of the choroid plexus, summarizes their changes in hydrocephalus, and analyzes the possibility of the choroid plexus as a therapeutic target for hydrocephalus.
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Affiliation(s)
- Ziang Deng
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Haoxiang Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Kunhong Zhong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuanyou Li
- Department of Pediatric Neurosurgery, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Huajiang Deng
- Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou City, China
| | - Baocheng Gao
- Department of Neurosurgery, The First People'S Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology) Kunming, Yunan, China
| | - Keru Huang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
- Department of Neurosurgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China.
- Department of Neurosurgery, The Fifth People's Hospital of Ningxia, Shizuishan, China.
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Ahlström FH, Viisanen H, Karhinen L, Velagapudi V, Blomqvist KJ, Lilius TO, Rauhala PV, Kalso EA. Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats. IBRO Neurosci Rep 2024; 17:38-51. [PMID: 38933596 PMCID: PMC11201153 DOI: 10.1016/j.ibneur.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.
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Affiliation(s)
- Fredrik H.G. Ahlström
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Hanna Viisanen
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Leena Karhinen
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, University of Helsinki, P.O. Box 20, FI-00014, Finland
| | - Kim J. Blomqvist
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Tuomas O. Lilius
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Tukholmankatu 8C, 00014, Finland
- Department of Emergency Medicine and Services, University of Helsinki and HUS Helsinki University Hospital, Haartmaninkatu 4, Helsinki 00290, Finland
| | - Pekka V. Rauhala
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Eija A. Kalso
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- SleepWell Research Programme, Faculty of Medicine, , University of Helsinki, Haartmaninkatu 3, 00014, Finland
- Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital and University of Helsinki, HUS, Stenbäckinkatu 9, P.O. Box 440, 00029, Finland
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Ye XF, Huang ZP, Li MM, Liu SF, Huang WL, Hamud AMS, Ye LC, Li LY, Wu SJ, Zhuang JL, Chen YH, Chen XR, Lin S, Wei XF, Chen CN. Update on aquaporin-4 antibody detection: the early diagnosis of neuromyelitis optica spectrum disorders. Mult Scler Relat Disord 2024; 90:105803. [PMID: 39128164 DOI: 10.1016/j.msard.2024.105803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 07/06/2024] [Accepted: 08/03/2024] [Indexed: 08/13/2024]
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.
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Affiliation(s)
- Xiao-Fang Ye
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Zheng-Ping Huang
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Mi-Mi Li
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Shu-Fen Liu
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Wan-Li Huang
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Abdullahi Mukhtar Sheik Hamud
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Li-Chao Ye
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Lin-Yi Li
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Shu-Juan Wu
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China
| | - Jian-Long Zhuang
- Prenatal Diagnosis Centre, Quanzhou Women's and Children's Hospital, Quanzhou 362000, Fujian China
| | - Yan-Hong Chen
- Department of Neurology, Shishi General Hospital, Quanzhou 362000, Fujian Province, China
| | - Xiang-Rong Chen
- The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China; Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China; Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, Australia.
| | - Xiao-Feng Wei
- College of Materials Science and Engineering, Huaqiao University, Xiamen 361021, Fujian Province, China.
| | - Chun-Nuan Chen
- Department of Neurology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China; The Second Clinical Medical College of Fujian Medical University, Quanzhou 362000Fujian Province, China.
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8
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Murata EM, Pritschet L, Grotzinger H, Taylor CM, Jacobs EG. Circadian Rhythms Tied to Changes in Brain Morphology in a Densely Sampled Male. J Neurosci 2024; 44:e0573242024. [PMID: 39147588 PMCID: PMC11411591 DOI: 10.1523/jneurosci.0573-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 08/08/2024] [Accepted: 08/10/2024] [Indexed: 08/17/2024] Open
Abstract
Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed 40 MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.
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Affiliation(s)
- Elle M Murata
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, California 93106
| | - Laura Pritschet
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, California 93106
| | - Hannah Grotzinger
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, California 93106
| | - Caitlin M Taylor
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, California 93106
| | - Emily G Jacobs
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, California 93106
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California 93106
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9
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Xing Z, Pan L, Yu A, Zhang J, Dong C, Chen J, Xing W, He X, Zhang Z. Value of ultra-high b-value diffusion-weighted imaging for the evaluation of renal ischemia-reperfusion injury. Magn Reson Imaging 2024; 111:1-8. [PMID: 38574980 DOI: 10.1016/j.mri.2024.03.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024]
Abstract
To explore the feasibility of ultra-high b-value diffusion-weighted imaging (ubDWI) in assessment of renal IRI. Thirty-five rabbits were randomized into a control group (n = 7) and a renal IRI group (n = 28). The rabbits in the renal IRI group underwent left renal artery clamping for 60 min. Rabbits underwent axial ubDWI before and at 1, 12, 24, and 48 h after IRI. Apparent diffusion coefficient (ADCst) were calculated from ubDWI with two b-values (b = 0, 1000 s/mm2). Triexponential fits were applied to calculate the pure diffusion coefficients (D), perfusion-related diffusion coefficient (D⁎), and ultra-high ADC (ADCuh). The interobserver reproducibility were evaluated. The repeated measurement analysis of variance and Spearman correlation analysis was used for statistical analysis. The ADCst, D, and ADCuh values showed good reproducibility. The ADCst, D, and D⁎ values of renal Cortex (CO) and outer medulla (OM) significantly decreased after IRI (all P < 0.05). The ADCuh values significantly increased from pre-IRI to 1 h after IRI (P < 0.05) and significantly declined at 24 h and 48 h after IRI (all P < 0.05). ADCuh was strongly positively correlated with AQP-1 in the renal CO and OM (ρ = 0.643, P < 0.001; ρ = 0.662, P < 0.001, respectively). ubDWI can be used to non-invasively evaluate early renal IRI, ADCuh may be adopted to reflect AQP-1 expression.
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Affiliation(s)
- Zhaoyu Xing
- Department of Urology, Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Liang Pan
- Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Anding Yu
- Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jinggang Zhang
- Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Congsong Dong
- Department of Radiology, Affiliated Hospital 6 of Nantong University (Yancheng Third People's Hospital), Yancheng, China
| | - Jie Chen
- Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wei Xing
- Department of Radiology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of Urology, Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
| | - Zhiping Zhang
- Department of Radiology, Affiliated Hospital 6 of Nantong University (Yancheng Third People's Hospital), Yancheng, China.
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10
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Lee DH, Lee EC, Park SW, Lee JY, Lee MR, Oh JS. Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction. Int J Mol Sci 2024; 25:8752. [PMID: 39201439 PMCID: PMC11354389 DOI: 10.3390/ijms25168752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 09/02/2024] Open
Abstract
Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood-brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood-brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.
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Affiliation(s)
- Dong-Hun Lee
- Industry-Academic Cooperation Foundation, The Catholic University of Korea, 222, Banpo-daro, Seocho-gu, Seoul 06591, Republic of Korea
| | - Eun Chae Lee
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sang-Won Park
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, 271 Cheonbo-ro, Uijeongbu 11765, Republic of Korea
| | - Ji Young Lee
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, 271 Cheonbo-ro, Uijeongbu 11765, Republic of Korea
| | - Man Ryul Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Republic of Korea
| | - Jae Sang Oh
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, 271 Cheonbo-ro, Uijeongbu 11765, Republic of Korea
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11
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Mireles-Ramírez MA, Pacheco-Moises FP, González-Usigli HA, Sánchez-Rosales NA, Hernández-Preciado MR, Delgado-Lara DLC, Hernández-Cruz JJ, Ortiz GG. Neuromyelitis optica spectrum disorder: pathophysiological approach. Int J Neurosci 2024; 134:826-838. [PMID: 36453541 DOI: 10.1080/00207454.2022.2153046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 11/19/2022] [Accepted: 11/24/2022] [Indexed: 12/02/2022]
Abstract
Aim: To review the main pathological findings of Neuromyelitis Optica Spectrum Disorder (NMOSD) associated with the presence of autoantibodies to aquaporin-4 (AQP4) as well as the mechanisms of astrocyte dysfunction and demyelination. Methods: An comprehensive search of the literature in the field was carried out using the database of The National Center for Biotechnology Information from . Systematic searches were performed until July 2022. Results: NMOSD is an inflammatory and demyelinating disease of the central nervous system mainly in the areas of the optic nerves and spinal cord, thus explaining mostly the clinical findings. Other areas affected in NMOSD are the brainstem, hypothalamus, and periventricular regions. Relapses in NMOSD are generally severe and patients only partially recover. NMOSD includes clinical conditions where autoantibodies to aquaporin-4 (AQP4-IgG) of astrocytes are detected as well as similar clinical conditions where such antibodies are not detected. AQP4 are channel-forming integral membrane proteins of which AQ4 isoforms are able to aggregate in supramolecular assemblies termed orthogonal arrays of particles (OAP) and are essential in the regulation of water homeostasis and the adequate modulation of neuronal activity and circuitry. AQP4 assembly in orthogonal arrays of particles is essential for AQP4-IgG pathogenicity since AQP4 autoantibodies bind to OAPs with higher affinity than for AQP4 tetramers. NMOSD has a complex background with prominent roles for genes encoding cytokines and cytokine receptors. AQP4 autoantibodies activate the complement-mediated inflammatory demyelination and the ensuing damage to AQP4 water channels, leading to water influx, necrosis and axonal loss. Conclusions: NMOSD as an astrocytopathy is a nosological entity different from multiple sclerosis with its own serological marker: immunoglobulin G-type autoantibodies against the AQP4 protein which elicits a complement-dependent cytotoxicity and neuroinflammation. Some patients with typical manifestations of NMSOD are AQP4 seronegative and myelin oligodendrocyte glycoprotein positive. Thus, the detection of autoantibodies against AQP4 or other autoantibodies is crucial for the correct treatment of the disease and immunosuppressant therapy is the first choice.
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Affiliation(s)
- Mario A Mireles-Ramírez
- Department of Neurology, High Specialty Medical Unit, Western National Medical Center of the Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Fermín P Pacheco-Moises
- Department of Chemistry, University Center of Exact Sciences and Engineering; University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Héctor A González-Usigli
- Department of Neurology, High Specialty Medical Unit, Western National Medical Center of the Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Nayeli A Sánchez-Rosales
- Department of Neurology, High Specialty Medical Unit, Western National Medical Center of the Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | - Martha R Hernández-Preciado
- Department of Neurology, High Specialty Medical Unit, Western National Medical Center of the Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
| | | | - José J Hernández-Cruz
- Department of Philosophical and Methodological Disciplines and Service of Molecular Biology in medicine HC, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Genaro Gabriel Ortiz
- Department of Neurology, High Specialty Medical Unit, Western National Medical Center of the Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
- Department of Philosophical and Methodological Disciplines and Service of Molecular Biology in medicine HC, University Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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12
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Lau K, Kotzur R, Richter F. Blood-brain barrier alterations and their impact on Parkinson's disease pathogenesis and therapy. Transl Neurodegener 2024; 13:37. [PMID: 39075566 PMCID: PMC11285262 DOI: 10.1186/s40035-024-00430-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/11/2024] [Indexed: 07/31/2024] Open
Abstract
There is increasing evidence for blood-brain barrier (BBB) alterations in Parkinson's disease (PD), the second most common neurodegenerative disorder with rapidly rising prevalence. Altered tight junction and transporter protein levels, accumulation of α-synuclein and increase in inflammatory processes lead to extravasation of blood molecules and vessel degeneration. This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration, which contribute to neurodegeneration. Toxin exposure or α-synuclein over-expression in animal models has been shown to initiate similar pathologies, providing a platform to study underlying mechanisms and therapeutic interventions. Here we provide a comprehensive review of the current knowledge on BBB alterations in PD patients and how rodent models that replicate some of these changes can be used to study disease mechanisms. Specific challenges in assessing the BBB in patients and in healthy controls are discussed. Finally, a potential role of BBB alterations in disease pathogenesis and possible implications for therapy are explored. The interference of BBB alterations with current and novel therapeutic strategies requires more attention. Brain region-specific BBB alterations could also open up novel opportunities to target specifically vulnerable neuronal subpopulations.
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Affiliation(s)
- Kristina Lau
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Rebecca Kotzur
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559, Hannover, Germany
| | - Franziska Richter
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559, Hannover, Germany.
- Center for Systems Neuroscience, Hannover, Germany.
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13
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Namatame C, Abe Y, Miyasaka Y, Takai Y, Matsumoto Y, Takahashi T, Mashimo T, Misu T, Fujihara K, Yasui M, Aoki M. Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder. Int J Mol Sci 2024; 25:8169. [PMID: 39125739 PMCID: PMC11311328 DOI: 10.3390/ijms25158169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/24/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund's adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.
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Affiliation(s)
- Chihiro Namatame
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Yoichiro Abe
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshiki Miyasaka
- Laboratory of Reproductive Engineering, Institute of Experimental Animal Sciences, Osaka University Medical School, Suita 565-0871, Japan
| | - Yoshiki Takai
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Yuki Matsumoto
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Toshiyuki Takahashi
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
- Department of Neurology, National Hospital Organization Yonezawa Hospital, Yonezawa 992-1202, Japan
| | - Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Tatsuro Misu
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Kazuo Fujihara
- Department of Multiple Sclerosis & Therapeutics, Fukushima Medical University, Fukushima 960-1295, Japan
- Multiple Sclerosis & Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama 963-8563, Japan
| | - Masato Yasui
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
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14
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Castro-Arnau J, Chauvigné F, Toft-Bertelsen TL, Finn RN, MacAulay N, Cerdà J. Aqp4a and Trpv4 mediate regulatory cell volume increase for swimming maintenance of marine fish spermatozoa. Cell Mol Life Sci 2024; 81:285. [PMID: 38969941 PMCID: PMC11335209 DOI: 10.1007/s00018-024-05341-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/19/2024] [Accepted: 06/28/2024] [Indexed: 07/07/2024]
Abstract
Volume regulation is essential for cell homeostasis and physiological function. Amongst the sensory molecules that have been associated with volume regulation is the transient receptor potential vanilloid 4 (TRPV4), which is a non-selective cation channel that in conjunction with aquaporins, typically controls regulatory volume decrease (RVD). Here we show that the interaction between orthologous AQP4 (Aqp4a) and TRPV4 (Trpv4) is important for regulatory volume increase (RVI) in post-activated marine fish spermatozoa under high osmotic stress. Based upon electrophysiological, volumetric, and in vivo and ex vivo functional experiments using the pharmacological and immunological inhibition of Aqp4a and Trpv4 our model suggests that upon ejaculation and exposure to the hypertonic seawater, spermatozoon shrinkage is initially mediated by water efflux through Aqp1aa in the flagellar tail. The shrinkage results in an increase in intracellular Ca2+ concentration, and the activation of sperm motility and a Na+/K+/2Cl- (NKCC1) cotransporter. The activity of NKCC1 is required for the initiation of cell swelling, which secondarily activates the Aqp4a-Trpv4 complex to facilitate the influx of water via Aqp4a-M43 and Ca2+ via Trpv4 and L-type channels for the mediation of RVI. The inhibitory experiments show that blocking of each of these events prevents either shrinkage or RVI. Our data thus reveal that post-activated marine fish spermatozoa are capable of initiating RVI under a high hypertonic stress, which is essential for the maintenance of sperm motility.
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Affiliation(s)
- Júlia Castro-Arnau
- Institute of Marine Sciences, Spanish National Research Council (CSIC), Barcelona, 08003, Spain
- Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Bellaterra (Barcelona), 08193, Spain
- Department of Cell Biology & Physiology, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA
| | - François Chauvigné
- Institute of Marine Sciences, Spanish National Research Council (CSIC), Barcelona, 08003, Spain
- Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Bellaterra (Barcelona), 08193, Spain
| | | | - Roderick Nigel Finn
- Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Bellaterra (Barcelona), 08193, Spain
- Department of Biological Sciences, University of Bergen, Bergen, 5020, Norway
| | - Nanna MacAulay
- Department of Neuroscience, University of Copenhagen, Copenhagen N, 2200, Denmark
| | - Joan Cerdà
- Institute of Marine Sciences, Spanish National Research Council (CSIC), Barcelona, 08003, Spain.
- Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Bellaterra (Barcelona), 08193, Spain.
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15
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Mack AF, Bihlmaier R, Deffner F. Shifting from ependyma to choroid plexus epithelium and the changing expressions of aquaporin-1 and aquaporin-4. J Physiol 2024; 602:3097-3110. [PMID: 37975746 DOI: 10.1113/jp284196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023] Open
Abstract
The cells of the choroid plexus (CP) epithelium are specialized ependymal cells (ECs) but have distinct properties. The CP cells and ECs form single-cell sheets contiguous to each other at a transitional zone. The CP is underlined by a basal lamina and has barrier properties, whereas the ECs do not. The basal lamina of the CP is continuous with the glia limitans superficialis and, consequently, the CP stroma is continuous with the meninges along entering blood vessels. The CP has previously been reported to express aquaporin-1 (AQP1) mostly apically, and ECs show mostly basolateral aquaporin-4 (AQP4) expression. Recent evidence in various systems has shown that in changing conditions the expression and distribution of AQP4 can be modified, involving phosphorylation and calmodulin-triggered translocation. Studies on the human CP revealed that AQP4 is also expressed in some CP cells, which is likely to be increased during ageing based on mouse data. Moreover, subependymal astrocytic processes in the ependyma-CP transition, forming a glial plate around blood vessels and facing the CP stroma, were strongly positive for AQP4. We propose that the increased AQP4 expression might be a compensatory mechanism for the observed reduction in CSF production in the ageing human brain. The high AQP4 density in the transition zone might facilitate the transport of water into and out of the CP stroma and serve as a drainage and clearing pathway for metabolites in the CNS.
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Affiliation(s)
- Andreas F Mack
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Ronja Bihlmaier
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Felix Deffner
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Freiburg, Freiburg, Germany
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16
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Li J, Jia S, Song Y, Xu W, Lin J. Ginkgolide B can alleviate spinal cord glymphatic system dysfunction and provide neuroprotection in painful diabetic neuropathy rats by inhibiting matrix metalloproteinase-9. Neuropharmacology 2024; 250:109907. [PMID: 38492884 DOI: 10.1016/j.neuropharm.2024.109907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/02/2024] [Accepted: 03/10/2024] [Indexed: 03/18/2024]
Abstract
The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. β-Dystroglycan (β-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated β-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, β-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased β-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.
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Affiliation(s)
- Jiang Li
- Department of Anesthesiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
| | - Shuaiying Jia
- Department of Anesthesiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
| | | | - Wenmei Xu
- Department of Anesthesiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
| | - Jingyan Lin
- Department of Anesthesiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
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17
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Thipani Madhu M, Balaji O, Kandi V, Ca J, Harikrishna GV, Metta N, Mudamanchu VK, Sanjay BG, Bhupathiraju P. Role of the Glymphatic System in Alzheimer's Disease and Treatment Approaches: A Narrative Review. Cureus 2024; 16:e63448. [PMID: 39077280 PMCID: PMC11285013 DOI: 10.7759/cureus.63448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2024] [Indexed: 07/31/2024] Open
Abstract
Currently, there is unavailability of disease-modifying medication for Alzheimer's disease (AD), a debilitating neurological disorder. The pathogenesis of AD appears to be complex and could be influenced by the glymphatic system present in the central nervous system (CNS). Amyloid-beta (Aβ) and other metabolic wastes are eliminated from the brain interstitium by the glymphatic system, which encompasses perivascular channels and astroglial cells. Dysfunction of the glymphatic system, which could occur due to decreased aquaporin 4 (AQP4) expression, aging-related alterations in the human brain, and sleep disruptions, may contribute to the pathogenesis of AD and also accelerate the development of AD by causing a buildup of harmful proteins like Aβ. Promising approaches have been examined for reducing AD pathology, including non-pharmacological therapies that target glymphatic function, like exercise and sleep regulation. In addition, preclinical research has also demonstrated the therapeutic potential of pharmaceutical approaches targeted at augmenting AQP4-mediated glymphatic flow. To identify the precise processes driving glymphatic dysfunction in AD and to find new treatment targets, more research is required. Innovative diagnostic and treatment approaches for AD could be made possible by techniques such as dynamic contrast-enhanced MRI, which promises to evaluate glymphatic function in neurodegenerative diseases. Treatment options for AD and other neurodegenerative diseases may be improved by comprehending and utilizing the glymphatic system's function in preserving brain homeostasis and targeting the mechanisms involved in glymphatic functioning. This review intends to enhance the understanding of the complex link between AD and the glymphatic system and focuses on the function of AQP4 channels in promoting waste clearance and fluid exchange.
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Affiliation(s)
- Mansi Thipani Madhu
- Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
| | - Ojas Balaji
- Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
| | - Venkataramana Kandi
- Clinical Microbiology, Prathima Institute of Medical Sciences, Karimnagar, IND
| | - Jayashankar Ca
- Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
| | | | - Nirosha Metta
- Neurology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
| | | | - Bhangdiya G Sanjay
- Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
| | - Praful Bhupathiraju
- Internal Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, IND
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18
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes contributes to sex-specific behavioral deficits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.14.594147. [PMID: 38798398 PMCID: PMC11118421 DOI: 10.1101/2024.05.14.594147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with projections high in aquaporin-4 (AQP4) expression. These AQP4-rich projections facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in blood vessel function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to pronounced shifts in stress-coping behavior and working memory deficits in male -but not female- mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased various transcripts associated with blood vessel maintenance in astrocytes from males, but either had no effect on- or decreased- these genes in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small molecule fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC in males is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor. Collectively, these findings provide initial evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to behavioral and cognitive consequences following chronic stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Shobha Johnsamuel
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Lauren L Vollmer
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Alexander M Kuhn
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Eric S Wohleb
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
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19
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Murata EM, Pritschet L, Grotzinger H, Taylor CM, Jacobs EG. Circadian rhythms tied to changes in brain morphology in a densely-sampled male. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.10.588906. [PMID: 38645226 PMCID: PMC11030376 DOI: 10.1101/2024.04.10.588906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.
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Affiliation(s)
- Elle M. Murata
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, CA 93106
| | - Laura Pritschet
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, CA 93106
| | - Hannah Grotzinger
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, CA 93106
| | - Caitlin M. Taylor
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, CA 93106
| | - Emily G. Jacobs
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, CA 93106
- Neuroscience Research Institute, University of California, Santa Barbara, CA 93106
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20
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Yaghoobi Z, Seyed Bagher Nazeri SS, Asadi A, Derafsh E, Talebi Taheri A, Tamtaji Z, Dadgostar E, Rahmati-Dehkordi F, Aschner M, Mirzaei H, Tamtaji OR, Nabavizadeh F. Non-coding RNAs and Aquaporin 4: Their Role in the Pathogenesis of Neurological Disorders. Neurochem Res 2024; 49:583-596. [PMID: 38114727 DOI: 10.1007/s11064-023-04067-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 12/21/2023]
Abstract
Neurological disorders are a major group of non-communicable diseases affecting quality of life. Non-Coding RNAs (ncRNAs) have an important role in the etiology of neurological disorders. In studies on the genesis of neurological diseases, aquaporin 4 (AQP4) expression and activity have both been linked to ncRNAs. The upregulation or downregulation of several ncRNAs leads to neurological disorder progression by targeting AQP4. The role of ncRNAs and AQP4 in neurological disorders is discussed in this review.
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Affiliation(s)
- Zahra Yaghoobi
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran
| | | | - Amir Asadi
- Psychiatry and Behavioral Sciences Research Center, School of Medicine, Addiction Institute, and Department of Psychiatry, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ehsan Derafsh
- Windsor University School of Medicine, Cayon, St Kitts and Nevis
| | - Abdolkarim Talebi Taheri
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Tamtaji
- Student Research Committee, Kashan University of Medical Sciences, Kashan, I.R. of Iran
| | - Ehsan Dadgostar
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. of Iran
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, I.R. of Iran
| | - Fatemeh Rahmati-Dehkordi
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. of Iran.
| | - Omid Reza Tamtaji
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
| | - Fatemeh Nabavizadeh
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, I.R. of Iran.
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21
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Alfieri L, Montana A, Frisoni P, D'Errico S, Neri M. Application of Aquaporins as Markers in Forensic Pathology: A Systematic Review of the Literature. Int J Mol Sci 2024; 25:2664. [PMID: 38473914 DOI: 10.3390/ijms25052664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
The study of aquaporins (AQPs) in various forensic fields has offered a promising horizon in response to the need to have reliable elements for the identification of the manner of death and for the individuation of forensic markers for the timing of lesions and vitality of injury. In the literature, various tissues have been studied; the most investigated are the lungs, brain, kidneys, skin, and blood vessels. A systematic literature review on PubMed following PRISMA 2020 guidelines enabled the identification of 96 articles. In all, 34 of these were enrolled to identify Aquaporin-like (AQP-like) forensic markers. The analysis of the literature demonstrated that the most significant markers among the AQPs are as follows: for the brain, AQP4, which is very important in brain trauma and hypoxic damage; AQP3 in the skin lesions caused by various mechanisms; and AQP5 in the diagnosis of drowning. Other applications are in organ damage due to drug abuse and thrombus dating. The focus of this review is to collect all the data present in the literature about the forensic application of AQPs as forensic markers in the most important fields of application. In the current use, the individuation, validation, and application of markers in forensic investigation are very useful in real forensic applications in cases evaluated in court.
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Affiliation(s)
- Letizia Alfieri
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Angelo Montana
- Department of Biomedical Sciences and Public Health, University Politecnica delle Marche, 60126 Ancona, Italy
| | - Paolo Frisoni
- Unit of Legal Medicine, AUSL Romagna, G.B. Morgagni-L. Pierantoni Hospital, 47100 Forlì, Italy
| | - Stefano D'Errico
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Margherita Neri
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
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22
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Markou A, Kitchen P, Aldabbagh A, Repici M, Salman MM, Bill RM, Balklava Z. Mechanisms of aquaporin-4 vesicular trafficking in mammalian cells. J Neurochem 2024; 168:100-114. [PMID: 38102893 PMCID: PMC10953025 DOI: 10.1111/jnc.16029] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/24/2023] [Accepted: 12/02/2023] [Indexed: 12/17/2023]
Abstract
The aquaporin-4 (AQP4) water channel is abundantly expressed in the glial cells of the central nervous system and facilitates brain swelling following diverse insults, such as traumatic injury or stroke. Lack of specific and therapeutic AQP4 inhibitors highlights the need to explore alternative routes to control the water permeability of glial cell membranes. The cell surface abundance of AQP4 in mammalian cells fluctuates rapidly in response to changes in oxygen levels and tonicity, suggesting a role for vesicular trafficking in its translocation to and from the cell surface. However, the molecular mechanisms of AQP4 trafficking are not fully elucidated. In this work, early and recycling endosomes were investigated as likely candidates of rapid AQP4 translocation together with changes in cytoskeletal dynamics. In transiently transfected HEK293 cells a significant amount of AQP-eGFP colocalised with mCherry-Rab5-positive early endosomes and mCherry-Rab11-positive recycling endosomes. When exposed to hypotonic conditions, AQP4-eGFP rapidly translocated from intracellular vesicles to the cell surface. Co-expression of dominant negative forms of the mCherry-Rab5 and -Rab11 with AQP4-eGFP prevented hypotonicity-induced AQP4-eGFP trafficking and led to concentration at the cell surface or intracellular vesicles respectively. Use of endocytosis inhibiting drugs indicated that AQP4 internalisation was dynamin-dependent. Cytoskeleton dynamics-modifying drugs also affected AQP4 translocation to and from the cell surface. AQP4 trafficking mechanisms were validated in primary human astrocytes, which express high levels of endogenous AQP4. The results highlight the role of early and recycling endosomes and cytoskeletal dynamics in AQP4 translocation in response to hypotonic and hypoxic stress and suggest continuous cycling of AQP4 between intracellular vesicles and the cell surface under physiological conditions.
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Affiliation(s)
- Andrea Markou
- College of Health and Life SciencesAston UniversityBirminghamUK
- School of Biosciences, Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
| | - Philip Kitchen
- College of Health and Life SciencesAston UniversityBirminghamUK
| | - Ahmed Aldabbagh
- College of Health and Life SciencesAston UniversityBirminghamUK
| | | | - Mootaz M. Salman
- Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
| | - Roslyn M. Bill
- College of Health and Life SciencesAston UniversityBirminghamUK
| | - Zita Balklava
- College of Health and Life SciencesAston UniversityBirminghamUK
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23
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Lapshina KV, Ekimova IV. Aquaporin-4 and Parkinson's Disease. Int J Mol Sci 2024; 25:1672. [PMID: 38338949 PMCID: PMC10855351 DOI: 10.3390/ijms25031672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/15/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
The water-selective channel aquaporin-4 (AQP4) is implicated in water homeostasis and the functioning of the glymphatic system, which eliminates various metabolites from the brain tissue, including amyloidogenic proteins. Misfolding of the α-synuclein protein and its post-translational modifications play a crucial role in the development of Parkinson's disease (PD) and other synucleopathies, leading to the formation of cytotoxic oligomers and aggregates that cause neurodegeneration. Human and animal studies have shown an interconnection between AQP4 dysfunction and α-synuclein accumulation; however, the specific role of AQP4 in these mechanisms remains unclear. This review summarizes the current knowledge on the role of AQP4 dysfunction in the progression of α-synuclein pathology, considering the possible effects of AQP4 dysregulation on brain molecular mechanisms that can impact α-synuclein modification, accumulation and aggregation. It also highlights future directions that can help study the role of AQP4 in the functioning of the protective mechanisms of the brain during the development of PD and other neurodegenerative diseases.
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Affiliation(s)
- Ksenia V. Lapshina
- Laboratory of Comparative Thermophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223 Saint Petersburg, Russia;
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24
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Silverglate B, Gao X, Lee HP, Maliha P, Grossberg GT. The aquaporin-4 water channel and updates on its potential as a drug target for Alzheimer's disease. Expert Opin Ther Targets 2023; 27:523-530. [PMID: 37475487 DOI: 10.1080/14728222.2023.2240017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 07/19/2023] [Indexed: 07/22/2023]
Abstract
INTRODUCTION Although there are several FDA-approved treatments for Alzheimer's disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD. AREAS COVERED We review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer's disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords 'Alzheimer's disease,' 'aquaporin-4,' 'neuromyelitis optica,' and their abbreviations. EXPERT OPINION We place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer's is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.
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Affiliation(s)
- Bret Silverglate
- Division of Geriatric Psychiatry, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - Xiaoyi Gao
- Division of Geriatric Psychiatry, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - Hannah P Lee
- Division of Geriatric Psychiatry, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - Peter Maliha
- Carolyn Wells-Peterson Geriatric Psychiatry Research Fellow, St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - George T Grossberg
- Division of Geriatric Psychiatry, St. Louis University School of Medicine, St. Louis, Missouri, USA
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25
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Garcia TA, Jonak CR, Binder DK. The Role of Aquaporins in Spinal Cord Injury. Cells 2023; 12:1701. [PMID: 37443735 PMCID: PMC10340765 DOI: 10.3390/cells12131701] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/08/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Edema formation following traumatic spinal cord injury (SCI) exacerbates secondary injury, and the severity of edema correlates with worse neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on plasma membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid, and ependyma around the central canal. Local expression at these tissue-fluid interfaces allows AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. In this review, we consider the available evidence regarding the potential role of AQP4 in edema after SCI. Although more work remains to be carried out, the overall evidence indicates a critical role for AQP4 channels in edema formation and resolution following SCI and the therapeutic potential of AQP4 modulation in edema resolution and functional recovery. Further work to elucidate the expression and subcellular localization of AQP4 during specific phases after SCI will inform the therapeutic modulation of AQP4 for the optimization of histological and neurological outcomes.
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Affiliation(s)
- Terese A. Garcia
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA
| | - Carrie R. Jonak
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA
| | - Devin K. Binder
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA
- Center for Glial-Neuronal Interactions, University of California, Riverside, CA 92521, USA
- Neuroscience Graduate Program, University of California, Riverside, CA 92521, USA
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26
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Surya W, Yong CPY, Tyagi A, Bhushan S, Torres J. Anomalous Oligomerization Behavior of E. coli Aquaporin Z in Detergent and in Nanodiscs. Int J Mol Sci 2023; 24:ijms24098098. [PMID: 37175807 PMCID: PMC10178869 DOI: 10.3390/ijms24098098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Aquaporins are tetrameric integral membrane proteins that act as water channels, and can also permeabilize membranes to other solutes. The monomer appears to be the functional form despite all aquaporins being organized as tetramers, which therefore must provide a clear functional advantage. In addition to this quaternary organization, some aquaporins can act as adhesion molecules in membrane junctions, when tetramers located in opposing membranes interact via their extracellular domains. These stacked forms have been observed in a range of aquaporins, whether using lipidic membrane environments, in electron crystallography, or using detergent micelles, in single-particle cryo-electron microscopy (cryo-EM). In the latter technique, structural studies can be performed when the aquaporin is reconstituted into nanodiscs of lipids that are surrounded by a protein scaffold. During attempts to study E. coli Aquaporin Z (AqpZ), we have found that in some conditions these nanodiscs tend to form filaments that appear to be either thicker head-to-tail or thinner side-to-side stacks of nanodiscs. Nanodisc oligomerization was observed using orthogonal analytical techniques analytical ultra-centrifugation and mass photometry, although the nature of the oligomers (head-to-tail or side-to-side) could not be determined. Using the latter technique, the AqpZ tetramer itself formed oligomers of increasing size when solubilized only in detergent, which is consistent with multiple stacking of AqpZ tetramers. We observed images consistent with both of these filaments in negative staining EM conditions, but only thicker filaments in cryo-EM conditions. We hypothesize that the apparent nanodisc side-to-side arrangement that can only be visualized in negative staining conditions is related to artifacts due to the sample preparation. Filaments of any kind were not observed in EM when nanodiscs did not contain AqpZ, or after addition of detergent into the nanodisc cryo-EM preparation, at concentrations that did not disrupt nanodisc formation. To our knowledge, these filaments have not been observed in nanodiscs preparations of other membrane proteins. AqpZ, like other aquaporins has a charge asymmetry between the cytoplasmic (more positive) and the extracellular sides, which may explain the likely head-to-tail stacking observed, both in nanodisc preparations and also in detergent micelles.
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Affiliation(s)
- Wahyu Surya
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Clare Pei Yii Yong
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Anu Tyagi
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Shashi Bhushan
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Jaume Torres
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
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27
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Thangaleela S, Sivamaruthi BS, Radha A, Kesika P, Chaiyasut C. Neuromyelitis Optica Spectrum Disorders: Clinical Perspectives, Molecular Mechanisms, and Treatments. APPLIED SCIENCES 2023; 13:5029. [DOI: 10.3390/app13085029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Neuromyelitis optica (NMO) is a rare autoimmune inflammatory disorder affecting the central nervous system (CNS), specifically the optic nerve and the spinal cord, with severe clinical manifestations, including optic neuritis (ON) and transverse myelitis. Initially, NMO was wrongly understood as a condition related to multiple sclerosis (MS), due to a few similar clinical and radiological features, until the discovery of the AQP4 antibody (NMO-IgG/AQP4-ab). Various etiological factors, such as genetic-environmental factors, medication, low levels of vitamins, and others, contribute to the initiation of NMO pathogenesis. The autoantibodies against AQP4 target the AQP4 channel at the blood–brain barrier (BBB) of the astrocyte end feet, which leads to high permeability or leakage of the BBB that causes more influx of AQP4-antibodies into the cerebrospinal fluid (CSF) of NMO patients. The binding of AQP4-IgG onto the AQP4 extracellular epitopes initiates astrocyte damage through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Thus, a membrane attack complex is formed due to complement cascade activation; the membrane attack complex targets the AQP4 channels in the astrocytes, leading to astrocyte cell damage, demyelination of neurons and oligodendrocytes, and neuroinflammation. The treatment of NMOSD could improve relapse symptoms, restore neurological functions, and alleviate immunosuppression. Corticosteroids, apheresis therapies, immunosuppressive drugs, and B cell inactivating and complement cascade blocking agents have been used to treat NMOSD. This review intends to provide all possible recent studies related to molecular mechanisms, clinical perspectives, and treatment methodologies of the disease, particularly focusing on recent developments in clinical criteria and therapeutic formulations.
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Affiliation(s)
- Subramanian Thangaleela
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | | | - Arumugam Radha
- Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620024, India
| | - Periyanaina Kesika
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chaiyavat Chaiyasut
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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Aquaporin-1 and Aquaporin-4 Expression in Ependyma, Choroid Plexus and Surrounding Transition Zones in the Human Brain. Biomolecules 2023; 13:biom13020212. [PMID: 36830582 PMCID: PMC9953559 DOI: 10.3390/biom13020212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
Abstract
The choroid plexus (CP) is a structure in the brain ventricles that produces the main part of the cerebrospinal fluid (CSF). It is covered with specialized cells which show epithelial characteristics and are the site of the blood-CSF barrier. These cells form a contiguous cell sheet with ventricle-lining ependymal cells which are known to express aquaporin-4 (AQP4). In contrast, CP epithelial cells express aquaporin-1 (AQP1) apically. We investigated the expression patterns of aquaporins in the CP-ependyma transition from human body donors using immunofluorescence and electron microscopy. Ependymal cells and subependymal astrocytes at the base of the CP showed a particularly high AQP4 immunoreactivity. Astrocytic processes formed a dense meshwork or glial plate around the blood vessels entering the CP. Interestingly, some of these astrocytic processes were in direct contact with the CP stroma, which contains fenestrated blood vessels, separated only by a basal lamina. Electron microscopy confirmed the continuity of the subastrocytic basal lamina with the CP epithelium. We also probed for components of the AQP4 anchoring dystrophin-dystroglycan complex. Immunolabeling for dystrophin and AQP4 showed an overlapping staining pattern in the glial plate but not in previously reported AQP4-positive CP epithelial cells. In contrast, dystroglycan expression was associated with laminin staining in the glial plate and the CP epithelium. This suggests different mechanisms for AQP4 anchoring in the cell membrane. The high AQP4 density in the connecting glial plate might facilitate the transport of water in and out of the CP stroma and could possibly serve as a drainage and clearing pathway for metabolites.
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29
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Aslesh T, Al-aghbari A, Yokota T. Assessing the Role of Aquaporin 4 in Skeletal Muscle Function. Int J Mol Sci 2023; 24:ijms24021489. [PMID: 36675000 PMCID: PMC9865462 DOI: 10.3390/ijms24021489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/09/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Water transport across the biological membranes is mediated by aquaporins (AQPs). AQP4 and AQP1 are the predominantly expressed AQPs in the skeletal muscle. Since the discovery of AQP4, several studies have highlighted reduced AQP4 levels in Duchenne muscular dystrophy (DMD) patients and mouse models, and other neuromuscular disorders (NMDs) such as sarcoglycanopathies and dysferlinopathies. AQP4 loss is attributed to the destabilizing dystrophin-associated protein complex (DAPC) in DMD leading to compromised water permeability in the skeletal muscle fibers. However, AQP4 knockout (KO) mice appear phenotypically normal. AQP4 ablation does not impair physical activity in mice but limits them from achieving the performance demonstrated by wild-type mice. AQP1 levels were found to be upregulated in DMD models and are thought to compensate for AQP4 loss. Several groups investigated the expression of other AQPs in the skeletal muscle; however, these findings remain controversial. In this review, we summarize the role of AQP4 with respect to skeletal muscle function and findings in NMDs as well as the implications from a clinical perspective.
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Affiliation(s)
- Tejal Aslesh
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada
| | - Ammar Al-aghbari
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada
| | - Toshifumi Yokota
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada
- The Friends of Garret Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, 8812 112 St., Edmonton, AB T6G 2H7, Canada
- Correspondence: ; Tel.: +1-(780)-492-1102
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Wang R, Peng L, Xiao Y, Zhou Q, Wang Z, Tang L, Xiao H, Yang K, Liu H, Li L. Single-cell RNA sequencing reveals changes in glioma-associated macrophage polarization and cellular states of malignant gliomas with high AQP4 expression. Cancer Gene Ther 2023; 30:716-726. [PMID: 36599974 DOI: 10.1038/s41417-022-00582-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 12/01/2022] [Accepted: 12/20/2022] [Indexed: 01/05/2023]
Abstract
Glioma is the most common primary central nervous system tumor in adults. Aquaporin-4, as a water channel protein encoded by AQP4 in the brain, is reported to alter its aggregation status to affect plasma membrane dynamics and provide the potential for metastasis of tumor cells and components of the tumor microenvironment. We performed single-cell RNA transcriptome sequencing of 53059 cells from 13 malignant glioma samples and spotted that the expression of AQP4 differed between samples. The same result was observed in the TCGA glioma database, showing poor overall survival and poor response to chemotherapy in AQP4 overexpressed populations. Concomitant with the overexpression of AQP4, genes related to the immune system were also over-expressed, such as CD74, HES1, CALD1, and HEBP2, indicating AQP4 may relate to immune factors of tumor progression. We also found that tumor-associated macrophages tended to polarize toward M2 macrophages in the high AQP4 group. In glioblastoma samples, we examined cell status differences and identified that cell status differs according to AQP4 expression levels. Briefly, our study revealed substantial heterogeneity within malignant gliomas with different AQP4 expression levels, indicating the intricate connection between tumor cells and the tumor immune environment.
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Affiliation(s)
- Ran Wang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu Peng
- Department of Clinical Laboratory, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yong Xiao
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qi Zhou
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhen Wang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Tang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Xiao
- Department of Neuro-Psychiatric Institute, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Kun Yang
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hongyi Liu
- Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Li Li
- Department of Laboratory Medicine, Shanghai General Hospital of Nanjing Medical University, Shanghai, China.
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31
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Li X, Yang B. Non-Transport Functions of Aquaporins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:65-80. [PMID: 36717487 DOI: 10.1007/978-981-19-7415-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Although it has been more than 20 years since the first aquaporin was discovered, the specific functions of many aquaporins are still under investigation, because various mice lacking aquaporins have no significant phenotypes. And in many studies, the function of aquaporin is not directly related to its transport function. Therefore, this chapter will focus on some unexpected functions of aquaporins, such the decreased tumor angiogenesis in AQP1 knockout mice, and AQP1 promotes cell migration, possibly by accelerating the water transport in lamellipodia of migrating cells. AQP transports glycerol, and water regulates glycerol content in epidermis and fat, thereby regulating skin hydration/biosynthesis and fat metabolism. AQPs may also be involved in neural signal transduction, cell volume regulation, and organelle physiology. AQP1, AQP3, and AQP5 are also involved in cell proliferation. In addition, AQPs have also been reported to play roles in inflammation in various tissues and organs. The functions of these AQPs may not depend on the permeability of small molecules such as water and glycerol, suggesting AQPs may play more roles in different biological processes in the body.
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Affiliation(s)
- Xiaowei Li
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Baoxue Yang
- School of Basic Medical Sciences, Peking University, Beijing, China.
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32
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Xiao M, Hou J, Xu M, Li S, Yang B. Aquaporins in Nervous System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1398:99-124. [PMID: 36717489 DOI: 10.1007/978-981-19-7415-1_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the nine AQPs expressed in the CNS, which include five members of aquaporin subfamily: AQP1, AQP4, AQP5, AQP6, and AQP8; three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP9; and one member of superaquaporin subfamily: AQP11. In addition, AQP1, AQP2, and AQP4 expressed in the peripheral nervous system are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica, brain tumors, and neurodegenerative disorders. Moreover, AQP4 has been demonstrated as a functional regulator of recently discovered glymphatic system that is a main contributor to clearance of toxic macromolecule from the brain. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.
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Affiliation(s)
- Ming Xiao
- Jiangsu Province, Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Jiaoyu Hou
- Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mengmeng Xu
- Basic Medical College, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Shao Li
- Department of Physiology, Dalian Medical University, Dalian, China
| | - Baoxue Yang
- School of Basic Medical Sciences, Peking University, Beijing, China.
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33
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Munera M, Buendía E, Sanchez A, Viasus D, Sanchez J. AQP4 as a vintage autoantigen: what do we know till now? Heliyon 2022; 8:e12132. [PMID: 36506380 PMCID: PMC9730132 DOI: 10.1016/j.heliyon.2022.e12132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 09/09/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Affiliation(s)
- M. Munera
- Medical Research Group (GINUMED), Universitary Corporation Rafael Nuñez, Colombia,Corresponding author.
| | - E. Buendía
- Faculty of Medicine, University of Cartagena, Cartagena, Colombia,Department of Internal Medicine, Centro Hospitalario Serena del Mar, Cartagena, Colombia,Clinical and Biomedical Research Group, Faculty of Medicine, University of Cartagena, Colombia
| | - A. Sanchez
- Faculty of Medicine, University of Cartagena, Cartagena, Colombia,Clinical and Biomedical Research Group, Faculty of Medicine, University of Cartagena, Colombia
| | - D. Viasus
- Division of Health Sciences, Universidad del Norte, Barranquilla, Colombia
| | - J. Sanchez
- Group of Clinical and Experimental Allergy (GACE), IPS Universitaria, University of Antioquia, Medellín, Colombia
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Kataoka M, Ikkou S, Kato Y, Minami K, Higashino H, Takagi T, Yamashita S. Effects of Ingested Water Volume on Oral Absorption of Fenofibrate, a BCS Class II Drug, from Micronized and Amorphous Solid Dispersion Formulations in Rats. Biol Pharm Bull 2022; 45:1452-1457. [PMID: 36184502 DOI: 10.1248/bpb.b22-00219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL). FEN absorption improvement by particle size reduction and the linearity in oral absorption by dose escalation suggested that the rate-limiting step of FEN absorption in rats was the dissolution rate, consistent with that in humans. When FEN, as an amorphous solid dispersion (ASD) formulation, was suspended in water followed by immediate administration, oral FEN absorption was significantly higher than when administered in crystalline form and was not influenced by the differences in ingested water volume. Oral absorption of FEN from encapsulated ASD formulation in 1 or 2 mL of water was comparable with that of the suspension form. However, 0.5 mL of water significantly reduced the oral absorption of the solid ASD FEN formulation. These results indicate that to improve the oral absorption of poorly water-soluble drugs when performing a preclinical study with rats, 1 mL of water is the minimum preferable ingested volume to evaluate in vivo formulation performance.
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Affiliation(s)
| | - Sakiho Ikkou
- Faculty of Pharmaceutical Sciences, Setsunan University
| | - Yuki Kato
- Faculty of Pharmaceutical Sciences, Setsunan University
| | - Keiko Minami
- Faculty of Pharmaceutical Sciences, Setsunan University
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35
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Ochoa-de la Paz LD, Gulias-Cañizo R. Glia as a key factor in cell volume regulation processes of the central nervous system. Front Cell Neurosci 2022; 16:967496. [PMID: 36090789 PMCID: PMC9453262 DOI: 10.3389/fncel.2022.967496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/03/2022] [Indexed: 11/23/2022] Open
Abstract
Brain edema is a pathological condition with potentially fatal consequences, related to cerebral injuries such as ischemia, chronic renal failure, uremia, and diabetes, among others. Under these pathological states, the cell volume control processes are fully compromised, because brain cells are unable to regulate the movement of water, mainly regulated by osmotic gradients. The processes involved in cell volume regulation are homeostatic mechanisms that depend on the mobilization of osmolytes (ions, organic molecules, and polyols) in the necessary direction to counteract changes in osmolyte concentration in response to water movement. The expression and coordinated function of proteins related to the cell volume regulation process, such as water channels, ion channels, and other cotransport systems in the glial cells, and considering the glial cell proportion compared to neuronal cells, leads to consider the astroglial network the main regulatory unit for water homeostasis in the central nervous system (CNS). In the last decade, several studies highlighted the pivotal role of glia in the cell volume regulation process and water homeostasis in the brain, including the retina; any malfunction of this astroglial network generates a lack of the ability to regulate the osmotic changes and water movements and consequently exacerbates the pathological condition.
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Affiliation(s)
- Lenin David Ochoa-de la Paz
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
- Asociación para Evitar la Ceguera en México (APEC), Unidad de Investigación APEC-UNAM, Mexico
- *Correspondence: Lenin David Ochoa-de la Paz
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36
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Dan Q, Ma Z, Tan Y, Visar B, Chen L. AQP4 knockout promotes neurite outgrowth via upregulating GAP43 expression in infant rats with hypoxic-ischemic brain injury. IBRAIN 2022; 8:324-337. [PMID: 37786741 PMCID: PMC10528973 DOI: 10.1002/ibra.12062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 10/04/2023]
Abstract
Neonatal hypoxic-ischemic encephalopathy (NHIE) induces severe cerebral damage and neurological dysfunction, with seldom effective therapy. Aquaporin-4 (AQP4) is involved in aggravating brain damage induced by NHIE. This study aimed to investigate the role of AQP4 underlying the pathogenesis of NHIE. Neonatal Sprague-Dawley rats were used to establish neonatal hypoxic-ischemic (HI) models, and the expression of AQP4 in the cortex, hippocampus, and lung tissues was detected by real-time quantitative polymerase chain reaction as well as Western blot. Primary cortical neurons were cultured for the oxygen-glucose deprivation (OGD) model, and siRNA was used to silence the expression of AQP4. Immunostaining of Tuj1 was performed to observe the axonal growth. CRISPER/Cas9 technology was used to knock out AQP4. The results demonstrated that AQP4 was upregulated in the cortex, hippocampus, and lung tissues in neonatal rats with HI and OGD neurons. Besides, silencing AQP4 promoted axonal growth of OGD neurons, and AQP4 knockout notably improved long-term neurobehavioral impairment. Furthermore, GAP43 was found closely correlated with AQP4 via GeneMANIA prediction. Significant downregulation of GAP43 was induced in OGD neurons, while AQP4 knockout markedly upregulated its expression in rats. This indicated that the depletion of AQP4 may enhance axonal regeneration and promote the long-term neurobehavioral recovery associated with the upregulation of GAP43 expression.
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Affiliation(s)
- Qi‐Qin Dan
- National‐Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China HospitalSichuan UniversityChengduChina
| | - Zheng Ma
- National‐Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China HospitalSichuan UniversityChengduChina
| | - Ya‐Xin Tan
- National‐Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China HospitalSichuan UniversityChengduChina
| | - Belegu Visar
- Center for Epigenetics and Induced Pluripotent Stem Cells, Kennedy Krieger InstituteJohns Hopkins UniversityBaltimoreUSA
| | - Li Chen
- National‐Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China HospitalSichuan UniversityChengduChina
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The Water Transport System in Astrocytes–Aquaporins. Cells 2022; 11:cells11162564. [PMID: 36010640 PMCID: PMC9406552 DOI: 10.3390/cells11162564] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/26/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Highlights
(AQPs) are transmembrane proteins responsible for fast water movement across cell membranes, including those of astrocytes. The expression and subcellular localization of AQPs in astrocytes are highly dynamic under physiological and pathological conditions. Besides their primary function in water homeostasis, AQPs participate in many ancillary functions including glutamate clearance in tripartite synapses and cell migration. Abstract Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood–brain barrier, physically and metabolically supporting and communicating with neurons, regulating the formation and functions of synapses, and maintaining water homeostasis and the microenvironment in the brain. Aquaporins (AQPs) are transmembrane proteins responsible for fast water movement across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8 and AQP9) have been reported to be expressed in astrocytes, and the expressions and subcellular localizations of AQPs in astrocytes are highly correlated with both their physiological and pathophysiological functions. This review describes and summarizes the recent advances in our understanding of astrocytes and AQPs in regard to controlling water homeostasis in the brain. Findings regarding the features of different AQP subtypes, such as their expression, subcellular localization, physiological functions, and the pathophysiological roles of astrocytes are presented, with brain edema and glioma serving as two representative AQP-associated pathological conditions. The aim is to provide a better insight into the elaborate “water distribution” system in cells, exemplified by astrocytes, under normal and pathological conditions.
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38
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Renal water transport in health and disease. Pflugers Arch 2022; 474:841-852. [PMID: 35678906 PMCID: PMC9338902 DOI: 10.1007/s00424-022-02712-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/11/2022] [Accepted: 05/19/2022] [Indexed: 12/12/2022]
Abstract
Saving body water by optimal reabsorption of water filtered by the kidney leading to excretion of urine with concentrations of solutes largely above that of plasma allowed vertebrate species to leave the aquatic environment to live on solid ground. Filtered water is reabsorbed for 70% and 20% by proximal tubules and thin descending limbs of Henle, respectively. These two nephron segments express the water channel aquaporin-1 located along both apical and basolateral membranes. In the proximal tubule, the paracellular pathway accounts for at least 30% of water reabsorption, and the tight-junction core protein claudin-2 plays a key role in this permeability. The ascending limb of Henle and the distal convoluted tubule are impermeant to water and are responsible for urine dilution. The water balance is adjusted along the collecting system, i.e. connecting tubule and the collecting duct, under the control of arginine-vasopressin (AVP). AVP is synthesized by the hypothalamus and released in response to an increase in extracellular osmolality or stimulation of baroreceptors by decreased blood pressure. In response to AVP, aquaporin-2 water channels stored in subapical intracellular vesicles are translocated to the apical plasma membrane and raise the water permeability of the collecting system. The basolateral step of water reabsorption is mediated by aquaporin-3 and -4, which are constitutively expressed. Drugs targeting water transport include classical diuretics, which primarily inhibit sodium transport; the new class of SGLT2 inhibitors, which promotes osmotic diuresis and the non-peptidic antagonists of the V2 receptor, which are pure aquaretic drugs. Disturbed water balance includes diabetes insipidus and hyponatremias. Diabetes insipidus is characterized by polyuria and polydipsia. It is either related to a deficit in AVP secretion called central diabetes insipidus that can be treated by AVP analogs or to a peripheral defect in AVP response called nephrogenic diabetes insipidus. Diabetes insipidus can be either of genetic origin or acquired. Hyponatremia is a common disorder most often related to free water excess relying on overstimulated or inappropriate AVP secretion. The assessment of blood volume is key for the diagnosis and treatment of hyponatremia, which can be classified as hypo-, eu-, or hypervolemic.
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39
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Immuno-pathogenesis of neuromyelitis optica and emerging therapies. Semin Immunopathol 2022; 44:599-610. [DOI: 10.1007/s00281-022-00941-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/20/2022] [Indexed: 01/01/2023]
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Abe Y, Yasui M. Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System. Biomolecules 2022; 12:biom12040591. [PMID: 35454180 PMCID: PMC9030581 DOI: 10.3390/biom12040591] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/20/2022] Open
Abstract
Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. NMO-IgG is an excellent marker for distinguishing the disease from other inflammatory demyelinating diseases, such as multiple sclerosis. The unique higher-order structure of AQP4—called orthogonal arrays of particles (OAPs)—as well as its subcellular localization may play a crucial role in the pathogenesis of the disease. Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. This review focuses on the binding properties of antibodies that recognize the extracellular region of AQP4 and the characteristics of AQP4 that are implicated in the pathogenesis of NMOSD.
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Affiliation(s)
- Yoichiro Abe
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
- Keio University Global Research Institute, Tokyo 108-8345, Japan
- Correspondence: (Y.A.); (M.Y.); Tel.: +81-3-5363-3751 (M.Y.)
| | - Masato Yasui
- Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan
- Keio University Global Research Institute, Tokyo 108-8345, Japan
- Correspondence: (Y.A.); (M.Y.); Tel.: +81-3-5363-3751 (M.Y.)
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41
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Cellular Distribution of Brain Aquaporins and Their Contribution to Cerebrospinal Fluid Homeostasis and Hydrocephalus. Biomolecules 2022; 12:biom12040530. [PMID: 35454119 PMCID: PMC9025855 DOI: 10.3390/biom12040530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 01/19/2023] Open
Abstract
Brain aquaporins facilitate the movement of water between the four water compartments: blood, cerebrospinal fluid, interstitial fluid, and intracellular fluid. This work analyzes the expression of the four most abundant aquaporins (AQPs) (AQP1, AQP4, AQP9, and AQP11) in the brains of mice and discuss their contribution to hydrocephalus. We analyzed available data from single-cell RNA sequencing of the central nervous system of mice to describe the expression of aquaporins and compare their distribution with that based on qPCR, western blot, and immunohistochemistry assays. Expression of AQP1 in the apical cell membrane of choroid plexus epithelial cells and of AQP4 in ependymal cells, glia limitans, and astrocyte processes in the pericapillary end foot is consistent with the involvement of both proteins in cerebrospinal fluid homeostasis. The expression of both aquaporins compensates for experimentally induced hydrocephalus in the animals. Recent data demonstrate that hypoxia in aged animals alters AQP4 expression in the choroidal plexus and cortex, increasing the ventricle size and intraventricular pressure. Cerebral distensibility is reduced in parallel with a reduction in cerebrospinal fluid drainage and cognitive deterioration. We propose that aged mice chronically exposed to hypoxia represent an excellent experimental model for studying the pathophysiological characteristics of idiopathic normal pressure hydrocephalus and roles for AQPs in such disease.
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Wei T, Zhou M, Gu L, Yang H, Zhou Y, Li M. A Novel Gating Mechanism of Aquaporin-4 Water Channel Mediated by Blast Shockwaves for Brain Edema. J Phys Chem Lett 2022; 13:2486-2492. [PMID: 35271290 DOI: 10.1021/acs.jpclett.2c00321] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
As the principal water channel in the brain, aquaporin-4 (AQP4) plays a vital role in brain edema, but its role in blast brain edema is unclear. On the basis of molecular simulations, we reveal the atomically detailed picture of AQP4 in response to blast shockwaves. The results show that the shockwave alone closes the AQP4 channel; however, shock-induced bubble collapse opens it. The jet from bubble collapse forcefully increases the distance between helices and the tilt angles of six helices relative to the membrane vertical direction in a very short time. The average channel size increases about 2.6 times, and the water flux rate is nearly 20 times higher than for normal states. It is responsible for abnormal water transport and a potential cause of acute blast brain edema. Additionally, the open AQP4 channel quickly returns to its normal state, which is in turn helpful for edema absorption. Thus, a novel gating mechanism for AQP4 related to the secondary structure change has been provided, which is different from the previous residue-mediated gating mechanism.
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Affiliation(s)
- Tong Wei
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
- CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei 230026, China
| | - Mi Zhou
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
| | - Lingzhi Gu
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
| | - Hong Yang
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
| | - Yang Zhou
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
| | - Ming Li
- Institute of Chemical Materials, China Academy of Engineering and Physics, Mianyang 621900, China
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Ishida H, Vogel HJ, Conner AC, Kitchen P, Bill RM, MacDonald JA. Simultaneous binding of the N- and C-terminal cytoplasmic domains of aquaporin 4 to calmodulin. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2022; 1864:183837. [PMID: 34890582 DOI: 10.1016/j.bbamem.2021.183837] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/30/2021] [Accepted: 11/30/2021] [Indexed: 10/19/2022]
Abstract
Aquaporin 4 (AQP4) is a water transporting, transmembrane channel protein that has important regulatory roles in maintaining cellular water homeostasis. Several other AQP proteins exhibit calmodulin (CaM)-binding properties, and CaM has recently been implicated in the cell surface localization of AQP4. The objective of the present study was to assess the CaM-binding properties of AQP4 in detail. Inspection of AQP4 revealed two putative CaM-binding domains (CBDs) in the cytoplasmic N- and C-terminal regions, respectively. The Ca2+-dependent CaM-binding properties of AQP4 CBD peptides were assessed using fluorescence spectroscopy, isothermal titration calorimetry, and two-dimensional 1H, 15N-HSQC NMR with 15N-labeled CaM. The N-terminal CBD of AQP4 predominantly interacted with the N-lobe of CaM with a 1:1 binding ratio and a Kd of 3.4 μM. The C-terminal AQP4 peptide interacted with both the C- and N-lobes of CaM (2:1 binding ratio; Kd1: 3.6 μM, Kd2: 113.6 μM, respectively). A recombinant AQP4 protein domain (recAQP4CT, containing the entire cytosolic C-terminal sequence) bound CaM in a 1:1 binding mode with a Kd of 6.1 μM. A ternary bridging complex could be generated with the N- and C-lobes of CaM interacting simultaneously with the N- and C-terminal CBD peptides. These data support a unique adapter protein binding mode for CaM with AQP4.
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Affiliation(s)
- Hiroaki Ishida
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hans J Vogel
- Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Alex C Conner
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Philip Kitchen
- College of Health and Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Roslyn M Bill
- College of Health and Life Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
| | - Justin A MacDonald
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada.
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Dadgostar E, Rahimi S, Nikmanzar S, Nazemi S, Naderi Taheri M, Alibolandi Z, Aschner M, Mirzaei H, Tamtaji OR. Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target. Neurochem Res 2022; 47:860-871. [PMID: 35088218 DOI: 10.1007/s11064-021-03512-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/22/2022]
Abstract
Traumatic brain injury (TBI) is known as an acute degenerative pathology of the central nervous system, and has been shown to increase brain aquaporin 4 (AQP4) expression. Various molecular mechanisms affect AQP4 expression, including neuronal high mobility group box 1, forkhead box O3a, vascular endothelial growth factor, hypoxia-inducible factor-1 α (HIF-1 α) sirtuin 2, NF-κB, Malat1, nerve growth factor and Angiotensin II receptor type 1. In addition, inhibition of AQP4 with FK-506, MK-801 (indirectly by targeting N-methyl-D-aspartate receptor), inactivation of adenosine A2A receptor, levetiracetam, adjudin, progesterone, estrogen, V1aR inhibitor, hypertonic saline, erythropoietin, poloxamer 188, brilliant blue G, HIF-1alpha inhibitor, normobaric oxygen therapy, astaxanthin, epigallocatechin-3-gallate, sesamin, thaliporphine, magnesium, prebiotic fiber, resveratrol and omega-3, as well as AQP4 gene silencing lead to reduced edema upon TBI. This review summarizes current knowledge and evidence on the relationship between AQP4 and TBI, and the potential mechanisms involved.
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Affiliation(s)
- Ehsan Dadgostar
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Student Research Committee, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shiva Rahimi
- School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Shahin Nikmanzar
- Department of Neurosurgery, Iran University of Medical Sciences, Tehran, Iran
| | - Sina Nazemi
- Tracheal Disease Research Center (TDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojtaba Naderi Taheri
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Alibolandi
- Anatomical Science Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Omid Reza Tamtaji
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran.
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45
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Deffner F, Gleiser C, Mattheus U, Wagner A, Neckel PH, Fallier-Becker P, Hirt B, Mack AF. Aquaporin-4 expression in the human choroid plexus. Cell Mol Life Sci 2022; 79:90. [PMID: 35072772 PMCID: PMC8785037 DOI: 10.1007/s00018-022-04136-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/02/2022] [Accepted: 01/05/2022] [Indexed: 01/15/2023]
Abstract
The choroid plexus (CP) consists of specialized ependymal cells and underlying blood vessels and stroma producing the bulk of the cerebrospinal fluid (CSF). CP epithelial cells are considered the site of the internal blood-cerebrospinal fluid barrier, show epithelial characteristics (basal lamina, tight junctions), and express aquaporin-1 (AQP1) apically. In this study, we analyzed the expression of aquaporins in the human CP using immunofluorescence and qPCR. As previously reported, AQP1 was expressed apically in CP epithelial cells. Surprisingly, and previously unknown, many cells in the CP epithelium were also positive for aquaporin-4 (AQP4), normally restricted to ventricle-lining ependymal cells and astrocytes in the brain. Expression of AQP1 and AQP4 was found in the CP of all eight body donors investigated (3 males, 5 females; age 74–91). These results were confirmed by qPCR, and by electron microscopy detecting orthogonal arrays of particles. To find out whether AQP4 expression correlated with the expression pattern of relevant transport-related proteins we also investigated expression of NKCC1, and Na/K-ATPase. Immunostaining with NKCC1 was similar to AQP1 and revealed no particular pattern related to AQP4. Co-staining of AQP4 and Na/K-ATPase indicated a trend for an inverse correlation of their expression. We hypothesized that AQP4 expression in the CP was caused by age-related changes. To address this, we investigated mouse brains from young (2 months), adult (12 months) and old (30 months) mice. We found a significant increase of AQP4 on the mRNA level in old mice compared to young and adult animals. Taken together, we provide evidence for AQP4 expression in the CP of the aging brain which likely contributes to the water flow through the CP epithelium and CSF production. In two alternative hypotheses, we discuss this as a beneficial compensatory, or a detrimental mechanism influencing the previously observed CSF changes during aging.
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Affiliation(s)
- Felix Deffner
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Corinna Gleiser
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Ulrich Mattheus
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Andreas Wagner
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Peter H Neckel
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Petra Fallier-Becker
- Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany
| | - Bernhard Hirt
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany
| | - Andreas F Mack
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Österbergstr. 3, 72074, Tübingen, Germany.
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Szczygielski J, Kopańska M, Wysocka A, Oertel J. Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis. Front Neurol 2021; 12:767470. [PMID: 34966347 PMCID: PMC8710539 DOI: 10.3389/fneur.2021.767470] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022] Open
Abstract
In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.
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Affiliation(s)
- Jacek Szczygielski
- Department of Neurosurgery, Institute of Medical Sciences, University of Rzeszów, Rzeszów, Poland.,Department of Neurosurgery, Faculty of Medicine and Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Marta Kopańska
- Department of Pathophysiology, Institute of Medical Sciences, University of Rzeszów, Rzeszów, Poland
| | - Anna Wysocka
- Chair of Internal Medicine and Department of Internal Medicine in Nursing, Faculty of Health Sciences, Medical University of Lublin, Lublin, Poland
| | - Joachim Oertel
- Department of Neurosurgery, Faculty of Medicine and Saarland University Medical Center, Saarland University, Homburg, Germany
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Pan QL, Lin FX, Liu N, Chen RC. The role of aquaporin 4 (AQP4) in spinal cord injury. Biomed Pharmacother 2021; 145:112384. [PMID: 34915672 DOI: 10.1016/j.biopha.2021.112384] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022] Open
Abstract
Aquaporin-4 (AQP-4) is an aquaporin composed of six helical transmembrane domains and two highly conserved ASN-pro-ALA (NPA) motifs. It is strongly expressed in rodent and human spinal cord tissues and plays a key role in the pathological process after SCI. After SCI, edema, glial scarring, and inflammation can accelerate the progression of injury and lead to deterioration of function. Many studies have reported that AQP-4 plays an important role in SCI. In particular, it plays an important role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after SCI. Loss of AQP-4 has been associated with reduced spinal edema and improved prognosis after SCI in mice. In addition, downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI. There is a consensus from numerous studies that AQP-4 may be a potential target for SCI therapy, which guides the ongoing investigation for molecular therapy of SCI. Here, we review the structure of AQP-4, its expression in normal and damaged spinal cord, and its role in SCI, as well as discuss the theoretical basis for the treatment of SCI.
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Affiliation(s)
- Qi-Lin Pan
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou 342800, PR China; The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou 342800, PR China
| | - Fei-Xiang Lin
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou 342800, PR China; The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou 342800, PR China
| | - Ning Liu
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou 342800, PR China; The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou 342800, PR China
| | - Rong-Chun Chen
- Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou 342800, PR China; The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou 342800, PR China.
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A Cardioplegic Solution with an Understanding of a Cardiochannelopathy. Antioxidants (Basel) 2021; 10:antiox10121878. [PMID: 34942981 PMCID: PMC8698488 DOI: 10.3390/antiox10121878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/16/2021] [Accepted: 11/23/2021] [Indexed: 01/11/2023] Open
Abstract
Cardiac surgeries have been improved by accompanying developing cardioplegia solutions. However, the cardioplegia application presents an ongoing challenge with a view of a sufficiently restored cardiac function. In this review, we focus on the cardioplegia-induced mechanism and summarize the findings of studies undertaken to improve cardioprotective strategies. Currently, and somewhat surprisingly, relatively little is known about cardiac electrolyte regulation through channel physiology. We hope that an improved understanding of the electrolyte transport through ion channels/transporters and modulations of water channel aquaporins will provide an insight into cardiac channel physiology and a channel-based cardiac pathology of a cardiochannelopathy.
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Feige L, Zaeck LM, Sehl-Ewert J, Finke S, Bourhy H. Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis. Viruses 2021; 13:2364. [PMID: 34960633 PMCID: PMC8708193 DOI: 10.3390/v13122364] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/19/2022] Open
Abstract
The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood-brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.
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Affiliation(s)
- Lena Feige
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
| | - Luca M. Zaeck
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Julia Sehl-Ewert
- Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany;
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), Federal Institute of Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; (L.M.Z.); (S.F.)
| | - Hervé Bourhy
- Institut Pasteur, Université de Paris, Lyssavirus Epidemiology and Neuropathology, 28 Rue Du Docteur Roux, 75015 Paris, France;
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50
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Genel O, Pariante CM, Borsini A. The role of AQP4 in the pathogenesis of depression, and possible related mechanisms. Brain Behav Immun 2021; 98:366-377. [PMID: 34474133 DOI: 10.1016/j.bbi.2021.08.232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/02/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Modulation of the aquaporin 4 (AQP4) water-regulatory channel or production of autoantibodies against this protein have been implicated in a variety of neuropsychiatric conditions, and possible mechanisms have been proposed. However, the nature of the interaction between AQP4 expression and its implications in depression remain elusive. To our knowledge, this is the first review summarising data for the involvement of AQP4 in the context of depression and related mechanisms across a wide range of experimental studies: pre-clinical (KO and wild-type), post-mortem, ex vivo, and clinical studies in depression. Overall, preclinical AQP4 wild-type studies showed that exposure to stress or inflammation, used as models of depression, decreased AQP4 protein and gene expression in various brain regions, including prefrontal cortex (PFC), choroid plexus and, especially, hippocampus. In preclinical AQP4 KO studies, AQP4 expression is necessary to prevent the effect of stress and inflammation on reduced neurogenesis and gliogenesis, and increased apoptosis and depressive-like behaviours. While in post-mortem and ex vivo studies of depression AQP4 expression was usually decreased in the hippocampus, prefrontal cortex and locus coeruleus, in clinical studies, where mRNA AQP4 expression or serum AQP4 autoantibodies were measured, there were no differences in depressed patients when compared with controls. In the future, studies should further investigate the mechanisms underlying the action of AQP4, and continue exploring if AQP4 autoantibodies are either contributing or underlying mechanisms of depression, or whether they are simply a mechanism underlying other autoimmune conditions where depression is present.
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Affiliation(s)
- Oktay Genel
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; School of Medicine, Faculty of Life Sciences and Medicine, King's College London, UK
| | - Carmine M Pariante
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
| | - Alessandra Borsini
- Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.
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