Details of a Researcher - Abe, Yoichiro

Papers - Abe, Yoichiro

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Cooling-rate dependence of the cryopreservation of aquaporin-overexpressing cells with a non-permeable cryoprotectant

Matsuo S., Yamazaki K., Yasui M., Abe Y., Uchida T.

Cryobiology 119 2025.06

ISSN 00112240

Dehydration of intracellular water is an important factor in the cryopreservation of cells, but questions remain as to the appropriate amount and timing of dehydration and the detailed mechanism of the freezing process. Answering these questions will lead to improvements in cryopreservation methods that have remained unchanged for more than half a century and to an increase in the number of cell types that can be cryopreserved. Therefore, we aimed to reveal the time point when cells were dehydrated in their cooling process and how much their viabilities were improved by dehydration. We conducted cryopreservation experiments using cells with enhanced water permeability due to membrane overexpression of the water transport channel protein (AQP4). The AQP4-expressing cells or non-AQP4-expressing cells were cryopreserved under different cooling rates after addition of the membrane-permeable cryoprotectant (CPA) Me2SO, the non-membrane-permeable CPA trehalose, or no CPA. The results showed that no cryopreservation was successful without CPAs, even in the AQP4-expressing cells with increased water permeability. At slow freezing rates below 35 °C/min, viability with Me2SO was maintained with decreasing in the cooling rate, but with trehalose, the viability decreased. At cooling rates above 80 °C/min, the viability of AQP4-expressing cells was significantly higher than that of AQP4-non-expressing cells. These results suggest that dehydration due to the osmotic-pressure difference generated after extracellular freezing is fatal to cells.

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Loss of aquaporin-4 impairs cerebrospinal fluid solute clearance through cerebrospinal fluid drainage pathways

Kato D., Kameda H., Kinota N., Fujii T., Xiawei B., Simi Z., Takai Y., Chau S., Miyasaka Y., Mashimo T., Abe Y., Yasui M., Minowa K., Kudo K.

Scientific Reports 14 ( 1 ) 2024.12

The aquaporin-4 (AQP4) water channel is essential in neurofluid dynamics. AQP4 loss impairs solute exchange between the cerebrospinal fluid (CSF) and interstitial fluid (ISF). However, whether AQP4 expression affects solute clearance from the CSF space to the extracranial space remains unclear. This study aimed to investigate this using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) following the intrathecal administration of gadolinium-based contrast agents (GBCAs) to AQP4 knockout (KO) rats. AQP4 KO rats showed reduced efflux of intrathecal GBCAs to the extracranial spaces through CSF drainage pathways and increased retention of intrathecal GBCAs in the CSF space compared with the controls. These results suggest that AQP4 loss impairs solute clearance from the CSF space to the extracranial spaces via the CSF drainage pathways. This study revealed a close relationship between AQP4 expression and CSF solute clearance, contributing to a better understanding of the function of AQP4 in neurofluid dynamics.

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Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder

Namatame C., Abe Y., Miyasaka Y., Takai Y., Matsumoto Y., Takahashi T., Mashimo T., Misu T., Fujihara K., Yasui M., Aoki M.

International Journal of Molecular Sciences 25 ( 15 ) 2024.08

ISSN 16616596

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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A tyrosine-based YXXΦ motif regulates the degradation of aquaporin-4 via both lysosomal and proteasomal pathways and is functionally inhibited by a 10-amino-acid sequence within its C-terminus

Wang Y., Suzuki R., Fujii A., Ieki K., Goda W., Yasui M., Abe Y.

FEBS Journal (FEBS Journal) 290 ( 10 ) 2616 - 2635 2023

ISSN 1742464X

Aquaporin-4 (AQP4) is a dominant water channel in the brain and is expressed on astrocytic end-feet, mediating water homeostasis in the brain. AQP4 is a target of an inflammatory autoimmune disease, neuromyelitis optica spectrum disorders (NMOSD), that causes demyelination. An autoantibody recognizing the extracellular domains of AQP4, called NMO-IgG, is critically implicated in the pathogenesis of the disease. Complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in astrocytes are the primary causes of the disease, preceding demyelination and neuronal damage. Additionally, some cytotoxic effects of binding of NMO-IgG to AQP4, independent of CDC/ADCC, have been proposed. Antibody-induced endocytosis of AQP4 is thought to be involved in CDC/ADCC-independent cytotoxicity induced by the binding of NMO-IgG to AQP4. To clarify the mechanism responsible for antibody-induced endocytosis of AQP4, we investigated the subcellular localization and trafficking of AQP4, focusing on its C-terminal domain, by making a variety of deletion and substitution mutants of mouse AQP4. We found that a tyrosine-based YXXΦ motif in the C-terminal domain of AQP4 plays a critical role in the steady-state subcellular localization/turnover and antibody-induced endocytosis/lysosomal degradation of AQP4. Our results indicate that the YXXΦ motif has to escape the inhibitory effect of the C-terminal 10-amino-acid sequence and be located at an appropriate distance from the plasma membrane to act as a signal for lysosomal degradation of AQP4. In addition to lysosomal degradation, we demonstrated that the YXXΦ motif also functions as a signal to degrade AQP4 using proteasomes under specific conditions.

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Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System

Abe Y., Yasui M.

Biomolecules (Biomolecules) 12 ( 4 ) 2022.04

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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Quantitative measurement of diffusion-weighted imaging signal using expression-controlled aquaporin-4 cells: Comparative study of 2-compartment and diffusion kurtosis imaging models

Imaizumi A., Obata T., Kershaw J., Tachibana Y., Abe Y., Shibata S., Nitta N., Aoki I., Yasui M., Higashi T.

PLoS ONE (PLoS ONE) 17 ( 4 April ) 2022.04

ISSN 1932-6203

The purpose of this study was to compare parameter estimates for the 2-compartment and diffusion kurtosis imaging models obtained from diffusion-weighted imaging (DWI) of aquaporin-4 (AQP4) expression-controlled cells, and to look for biomarkers that indicate differences in the cell membrane water permeability. DWI was performed on AQP4-expressing and non-expressing cells and the signal was analyzed with the 2-compartment and diffusion kurtosis imaging models. For the 2-compartment model, the diffusion coefficients (Df, Ds) and volume fractions (Ff, Fs, Ff = 1-Fs) of the fast and slow compartments were estimated. For the diffusion kurtosis imaging model, estimates of the diffusion kurtosis (K) and corrected diffusion coefficient (D) were obtained. For the 2-compartment model, Ds and Fs showed clear differences between AQP4-expressing and non-expressing cells. Fs was also sensitive to cell density. There was no clear relationship with the cell type for the diffusion kurtosis imaging model parameters. Changes to cell membrane water permeability due to AQP4 expression affected DWI of cell suspensions. For the 2-compartment and diffusion kurtosis imaging models, Ds was the parameter most sensitive to differences in AQP4 expression.

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Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

Ishida K., Yamada K., Nishiyama R., Hashimoto T., Nishida I., Abe Y., Yasui M., Iwatsubo T.

Journal of Experimental Medicine (Journal of Experimental Medicine) 219 ( 3 ) 2022.03

ISSN 00221007

Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.

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Amyloid-β Clearance and its Evaluation by Auditory Stimulation in a Mouse Model of Alzheimer's Disease

Ogawa M., Mitsukura Y., Abe Y., Yasui M.

IECON Proceedings (Industrial Electronics Conference) 2022-October 2022

ISSN 21624704

The purpose of this study was to quantify the clearance of amyloid-β (Aβ) protein by auditory stimulation in a mouse model of Alzheimer's disease (AD). Accumulation of Aβ is thought to be one of the causes of AD. It has been confirmed that Aβ in 5XFAD mice, a mouse model of AD, is reduced by auditory stimulation at a period of 40 Hz, in which sounds are switched on and off 40 times per second. A previous study showed that auditory stimulation of 1-8 msec duration may be particularly effective for Aβ clearance. However, quantitative evaluation of Aβ has not yet been conducted. Therefore, in this study, we quantitatively evaluated the effect of auditory stimulation on Aβ clearance by analyzing the amount of Aβ. As a result, auditory stimulation using a sound with a period of 40 Hz, a pitch of 10 kHz, and a duration of 3 msec reduced the magnitude of Aβ.

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The α-dystrobrevins play a key role in maintaining the structure and function of the extracellular matrix–significance for protein elimination failure arteriopathies

Sharp M.M.G., Cassidy J., Thornton T., Lyles J., Keable A., Gatherer M., Yasui M., Abe Y., Shibata S., Weller R.O., Górecki D.C., Carare R.O.

Acta Neuropathologica Communications (Acta Neuropathologica Communications) 9 ( 1 ) 2021.12

ISSN 2051-5960

The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.

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Di-lysine motif-like sequences formed by deleting the C-terminal domain of aquaporin-4 prevent its trafficking to the plasma membrane

Chau S., Fujii A., Wang Y., Vandebroek A., Goda W., Yasui M., Abe Y.

Genes to Cells (Genes to Cells) 26 ( 3 ) 152 - 164 2021.03

ISSN 13569597

Aquaporin-4 is a transmembrane water channel protein, the C-terminal domain of which is facing the cytosol. In the process of investigating the role of the C-terminal domain of aquaporin-4 with regard to intracellular trafficking, we observed that a derivative of aquaporin-4, in which the C-terminal 53 amino acids had been removed (Δ271-323), was localized to intracellular compartments, including the endoplasmic reticulum, but was not expressed on the plasma membranes. This was determined by immunofluorescence staining and labeling of the cells with monoclonal antibody specifically recognizing the extracellular domain of aquaporin-4, followed by confocal microscopy and flow cytometry. Deletion of additional amino acids in the C-terminal domain of aquaporin-4 led to its redistribution to the plasma membrane. This suggests that the effect of the 53-amino acid deletion on the subcellular localization of aquaporin-4 could be attributed to the formation of a signal at the C terminus that retained aquaporin-4 in intracellular compartments, rather than the loss of a signal required for plasma membrane targeting. Substitution of the lysine at position 268 with alanine could rescue the Δ271-323-associated retention in the cytosol, suggesting that the C-terminal sequence of the mutant served as a signal similar to a di-lysine motif.

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Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model

Abe Y., Ikegawa N., Yoshida K., Muramatsu K., Hattori S., Kawai K., Murakami M., Tanaka T., Goda W., Goto M., Yamamoto T., Hashimoto T., Yamada K., Shibata T., Misawa H., Mimura M., Tanaka K.F., Miyakawa T., Iwatsubo T., Hata J.I., Niikura T., Yasui M.

Acta Neuropathologica Communications (Acta Neuropathologica Communications) 8 ( 1 ) 67 2020.05

Research paper (scientific journal), Joint Work, Accepted

© 2020 The Author(s). Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

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Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS

Hirose M., Asano M., Watanabe-Matsumoto S., Yamanaka K., Abe Y., Yasui M., Tokuda E., Furukawa Y., Misawa H.

Neuroscience Research (Neuroscience Research) 171 74 - 82 2020

ISSN 01680102

Overexpression and mislocalization of aquaporin-4 (AQP4) in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS) have previously been reported. However, how alterations of AQP4 affect interstitial bulk flow in the brain and spinal cord, the so-called glymphatic system, is unclear. Here, we report an enhanced accumulation of disease-associated SOD1 species including SOD1 oligomers in SOD1G93A;AQP4−/− mice compared with SOD1G93A mice during ALS disease progression, as analyzed by sandwich ELISA. By directly injecting SOD1 oligomers into the spinal cord parenchyma, we observed a significantly larger delay in clearance of biotinylated or fluorescent-labeled SOD1 oligomers in AQP4−/− mice than in wild-type mice. Furthermore, when we injected the fluorescent-labeled tracer protein ovalbumin into the cisterna magna and analyzed the tracer distribution in the cervical spinal cord, approximately 35 % processing ability was found to be reduced in SOD1G93A mice compared to wild-type mice. These results suggest that the glymphatic system is abnormal and that waste clearance is delayed in SOD1G93A mice.

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Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina

Ozawa Y., Toda E., Kawashima H., Homma K., Osada H., Nagai N., Abe Y., Yasui M., Tsubota K.

Molecular Neurobiology (Molecular Neurobiology) 56 ( 12 ) 8124 - 8135 2019.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 08937648

© 2019, The Author(s). The bidirectional water channel aquaporin 4 (AQP4) is abundantly expressed in the neural tissue. The advantages and disadvantages of AQP4 neural tissue deficiency under pathological conditions, such as inflammation, and relationship with neural diseases, such as Alzheimer’s disease, have been previously reported. However, the physiological functions of AQP4 are not fully understood. Here, we evaluated the role of AQP4 in the mouse retina using Aqp4 knockout (KO) mice. Aqp4 was expressed in Müller glial cells surrounding the synaptic area between photoreceptors and bipolar cells. Both scotopic and photopic electroretinograms showed hyperactive visual responses in KO mice, gradually progressing with age. Moreover, the amplitude reduction after frequent stimuli and synaptic fatigue was more severe in KO mice. Glutamine synthetase, glutamate aspartate transporter, synaptophysin, and the inward potassium channel Kir2.1, but not Kir4.1, were downregulated in KO retinas. KIR2.1 colocalized with AQP4 in Müller glial cells at the synaptic area, and its expression was affected by Aqp4 levels in primary Müller glial cell cultures. Intraocular injection of potassium in wild-type mice led to visual function hyperactivity, as observed in Aqp4 KO mice. Mitochondria molecules, such as Pgc1α and CoxIV, were downregulated, while apoptotic markers were upregulated in KO retinas. AQP4 may fine-tune synaptic activity, most likely by regulating potassium metabolism, at least in part, via collaborating with KIR2.1, and possibly indirectly regulating glutamate kinetics, to inhibit neural hyperactivity and synaptic fatigue which finally affect mitochondria and cause neurodegeneration.

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Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke

Monai H., Wang X., Yahagi K., Lou N., Mestre H., Xu Q., Abe Y., Yasui M., Iwai Y., Nedergaard M., Hirase H.

Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America) 166 ( 22 ) 11010 - 11019 2019.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 00278424

© 2019 National Academy of Sciences. All rights reserved. Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.

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Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Mestre H., Hablitz L., Xavier A., Feng W., Zou W., Pu T., Monai H., Murlidharan G., Rivera R., Simon M., Pike M., Plá V., Du T., Kress B., Wang X., Plog B., Thrane A., Lundgaard I., Abe Y., Yasui M., Thomas J., Xiao M., Hirase H., Asokan A., Iliff J., Nedergaard M.

eLife (eLife) 7 e40070 2018.12

Research paper (scientific journal), Joint Work, Accepted

© Mestre et al. The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

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Comparison of diffusion-weighted MRI and anti-Stokes Raman scattering (CARS) measurements of the inter-compartmental exchange-time of water in expression-controlled aquaporin-4 cells

Obata T, Kershaw J, Tachibana Y, Miyauchi T, Abe Y, Shibata S, Kawaguchi H, Ikoma Y, Takuwa H, Aoki I, Yasui M.

Scientific Reports (Scientific Reports) 8 ( 1 ) 17954 2018.12

Research paper (scientific journal), Joint Work, Accepted

© 2018, The Author(s). We performed multi-b and multi-diffusion-time diffusion-weighted magnetic resonance imaging on aquaporin-4-expressing (AQ) and -non-expressing (noAQ) cells, and demonstrated a clear difference between the signals from the two cell types. The data were interpreted using a two-compartment (intra and extracellular spaces) model including inter-compartmental exchange. It was also assumed that restricted diffusion of water molecules inside the cells leads to the intracellular diffusion coefficient being inversely proportional to the diffusion-time. Estimates of the water-exchange-times obtained with this model are compared to those measured using an independent optical imaging technique (coherent anti-Stokes Raman scattering imaging, CARS). For both techniques it was found that the exchange-time estimated for the noAQ cells was significantly longer than that for the AQ cells.

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Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis.

Watanabe-Matsumoto S, Moriwaki Y, Okuda T, Ohara S, Yamanaka K, Abe Y, Yasui M, Misawa H.

Neurosci. Res (Neuroscience Research) 133 48 - 57 2018.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 01680102

© 2017 Elsevier Ireland Ltd and Japan Neuroscience Society Aquaporin-4 (AQP4) is abundantly expressed in the central nervous system and is involved in the water balance in the cellular environment. Previous studies have reported that AQP4 expression is upregulated in rat models of amyotrophic lateral sclerosis (ALS), a fatal disease that affects motor neurons in the brain and spinal cord. In this study, we report that astrocytic AQP4 overexpression is evident during the course of disease in the spinal cord of an ALS mouse model, as well as in tissue from patients with ALS. AQP4 overexpression appears to be specifically associated with ALS because it was not induced by other experimental manipulations that produced acute or chronic gliosis. In order to examine the contribution of AQP4 to ALS disease development, we crossed AQP4 knockout mice with a mouse model of ALS. Significant improvement in blood-brain barrier (BBB) permeability was observed in the AQP4-deficient ALS mouse model. However, the time to disease onset and total lifespan were reduced in the AQP4-deficient ALS mouse model. The contradictory results suggest that changes in AQP4 may be context-dependent and further studies are required to understand the precise contribution of brain water balance in ALS.

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Alteration of global protein SUMOylation in neurons and astrocytes in response to Alzheimer's disease-associated insults.

Maruyama T, Wada H, Abe Y, Niikura T

Biochem. Biophys. Res. Commun. (Biochemical and Biophysical Research Communications) 500 ( 2 ) 470 - 475 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2018 Elsevier Inc. SUMOylation, a post-translational modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has been implicated in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), and in neuron- and astrocyte-specific physiological functions. Global SUMOylation is increased in the AD mouse brain in the pre-plaque-forming stage but returns to wild-type levels in the plaque-bearing stage. To clarify the reason for the transient change in SUMOylation, we analyzed the alteration of global SUMOylation induced by AD-associated cytotoxic stimuli in neurons and astrocytes individually. In neurons, amyloid β42 oligomers induced some but not significant increase in levels of SUMO1-modified proteins. Both hydrogen peroxide and glutamate significantly reduced SUMO1-modified protein levels. These changes were more prominent in neurons than in astrocytes. The opposite effect of Aβ and oxidative/excitotoxic stimuli on SUMO1 modification may cause the pathological stage-associated change in the level of SUMO-modified proteins in the AD mouse brain.

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SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein.

Maruyama T, Abe Y, Niikura T

Heliyon (Heliyon) 4 ( 4 ) e00601 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 24058440

© 2018 The Authors Amyloid β a key molecule in the pathogenesis of Alzheimer's disease (AD), is produced from amyloid precursor protein (APP) by the cleavage of secretases. APP is SUMOylated near the cleavage site of β-secretase. SUMOylation of APP reduces amyloid β production, but its regulatory system is still unclear. SUMOylation, a modification at a lysine residue of a target protein, is mediated by activating, conjugating, and ligating enzymes and is reversed by a family of sentrin/SUMO-specific proteases (SENPs). Here, we found that both SENP1 and SENP2 induced de-SUMOylation of APP. Using quantitative PCR, we also found that expression of SENP1 but not SENP2 increased in an age-dependent manner only in female mice. The results of immunoblot analyses showed that the protein expression was consistent with the PCR results. Females, compared to males, have a higher incidence of AD in humans and show more aggressive amyloid pathology in AD mouse models. Our results provide a clue to understanding the role of SUMOylation in the sex difference in AD pathogenesis.

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Humanin affects object recognition and gliosis in short-term cuprizone-treated mic.

Murakami M, Nagahama M, Abe Y, Niikura T.

Neuropeptides 66 90 - 96 2017.12

Research paper (scientific journal), Joint Work, Accepted

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The dual effect of the astrocyte-specific enhancer of the AQP4 M1 promoter

Abe Y, Goda W., Ikeshima-Kataoka H, Yasui M

FEBS Lett. 591 ( 23 ) 3906 - 3915 2017.12

Research paper (scientific journal), Joint Work, Accepted

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The binding property of a mAb against the extracellular domains of AQP4 directs AQP4 toward endocytosis.

Huang P#, Takai Y#, Kusano-Arai O, Ramadhanti J, Iwanari H, Miyauchi T, Sakihama T, Han H-Y, Aoki M, Hamakubo T, Fujihara K, Yasui M, Abe Y

Biochem. Biophys. Rep. 7 77 - 83 2016.09

Research paper (scientific journal), Joint Work, Accepted

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High avidity chimeric monoclonal antibodies against the extracellular domains of human aquaporin-4 competing with the neuromyelitis optica autoantibody, NMO-IgG

Miyazaki-Komine K, Takai Y, Huang P, Kusano-Arai O, Iwanari H, Misu T, Koda K, Mitomo K, Sakihama T, Toyama Y, Fujihara K, Hamakubo T, Yasui M, and Abe Y

Br. J. Pharmacol. 173 ( 1 ) 103 - 114 2016.01

Research paper (scientific journal), Joint Work, Accepted

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Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody

Kurosawa K, Misu T, Takai Y, Sato DK, Takahashi T, Abe Y, Iwanari H, Ogawa R, Nakashima I, Fujihara K, Hamakubo T, Yasui M, Aoki M.

Acta Neuropathol. Commun. 3 82 2015.12

Research paper (scientific journal), Accepted

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Dynamic subcellular localization of aquaporin-7 in white adipocytes.

Miyauchi T, Yamamoto H, Abe Y, Yoshida GJ, Rojek A, Sohara E, Uchida S., Nielsen S, Yasui M

FEBS Lett. 589 ( 5 ) 608 - 614 2015.02

Research paper (scientific journal), Joint Work, Accepted

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Aquaporin 4 dependent expression of GFAP and TN-C in activated astrocytes in stab wound mouse brain and in primary culture.

Ikeshima-Kataoka H, Abe Y, Yasui M

J. Neurosci. Res. 93 ( 1 ) 121 - 129 2015.01

Research paper (scientific journal), Joint Work, Accepted

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Sustained downregulation of β-dystroglycan and associated dysfunctions of astrocytic endfeet in epileptic cerebral cortex.

Gondo A, Shinotsuka T, Morita A, Abe Y, Yasui M, Nuriya M

J. Biol. Chem. 289 ( 44 ) 30279 - 30288 2014.10

Research paper (scientific journal), Joint Work, Accepted

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Expression and localization of aquaporin-4 in sensory ganglia.

Kato J, Takai Y, Hayashi, MK, Kato Y, Tanaka M, Sohma Y, Abe Y, Yasui M

Biochem. Biophys. Res. Commun. 451 ( 4 ) 562 - 567 2014.09

Research paper (scientific journal), Joint Work, Accepted

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SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants.

Niikura T, Kita Y, and Abe Y

PLOS ONE 9 ( 6 ) e101080 2014.06

Research paper (scientific journal), Joint Work, Accepted

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Unprecedented cell-selection using ultra-quick freezing combined with aquaporin expression.

Kato Y, Miyauchi T, Abe Y, Kojić D, Tanaka M, Chikazawa N, Nakatake Y, Ko SB, Kobayashi D, Hazama A, Fujiwara S, Uchida T, Yasui M

PLOS ONE 9 ( 2 ) e87644 2014.02

Research paper (scientific journal), Joint Work, Accepted

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Immunological function of aquaporin-4 in stab-wounded mouse brain in concert with a pro-inflammatory cytokine inducer, osteopontin.

Ikeshima-Kataoka H, Abe Y, Abe T, Yasui M

Mol. Cell. Neurosci. 56 65 - 75 2013.09

Research paper (scientific journal), Joint Work, Accepted

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A novel monoclonal antibody against the C-terminal region of aquaporin-4.

Ramadhanti J, Huang P, Kusano-Arai O, Iwanari H, Sakihama T, Misu T, Fujihara K, Hamakubo T, Yasui M, and Abe Y

Monoclon. Antib. Immunodiagn. Immunother. 32 ( 4 ) 270 - 276 2013.08

Research paper (scientific journal), Joint Work, Accepted

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Establishment of monoclonal antibodies against the extracellular domain that block binding of NMO-IgG to AQP4.

Miyazaki K, Abe Y, Iwanari H, Suzuki Y, Kikuchi T, Ito T, Kato J, Kusano-Arai O, Takahashi T, Nishiyama S, Ikeshima-Kataoka H, Tsuji S, Arimitsu T, Kato Y, Sakihama T, Toyama Y, Fujihara K, Hamakubo T, and Yasui, M

J. Neuroimmunol. 260 ( 1-2 ) 107 - 116 2013.07

Research paper (scientific journal), Joint Work, Accepted

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An astrocyte-specific enhancer of aquaporin-4 gene functions through a consensus sequence of POU transcription factors in concert with multiple upstream elements.

Abe Y, Ikeshima-Kataoka H, Goda W, Niikura T, and Yasui M

J. Neurochem. 120 ( 6 ) 899 - 912 2012.03

Research paper (scientific journal), Joint Work, Accepted

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Curcumin and genistein additively potentiate G551D-CFTR.

Yu Y-C, Miki H, Nakamura Y, Hanyuda A, Matsuzaki Y,Abe Y, Yasui M, Tanaka K, Hwang T-C, Gompadre SG, Sohma Y

J. Cyst. Fibros. 10 ( 4 ) 243 - 252 2011.07

Research paper (scientific journal), Joint Work, Accepted

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TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study.

Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, Hasegawa T

J. Clin. Endocrinol. Metab. 94 ( 4 ) 1317 - 1323 2009.04

Research paper (scientific journal), Joint Work, Accepted

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Phosphorylation in the C-terminal domain of aquaporin-4 is required for Golgi transition in primary cultured astrocytes.

Kadohira I, Abe Y, Nuriya M, Sano K, Tsuji S, Arimitsu T, Yoshimura Y, and Yasui M

Biochem. Biophys. Res. Commun. 377 ( 2 ) 463 - 468 2008.11

Research paper (scientific journal), Joint Work, Accepted

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Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol uptake/transporter 1, acts as a negative regulator for N-terminal palmitoylation of Sonic hedgehog.

Abe Y,Kita Y, and Niikura T

FEBS J. 275 ( 2 ) 318 - 338 2008.02

Research paper (scientific journal), Joint Work, Accepted

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Cytotoxic mechanisms by M239V presenilin 2, a little analyzed Alzheimer’s disease-causative mutant.

Abe Y, Hashimoto Y, Tomita Y, Terashita K, Aiso S, Tajima H, Niikura T, Matsuoka M, Nishimoto I

J. Neurosci. Res. 77 ( 4 ) 583 - 595 2004.08

Research paper (scientific journal), Joint Work, Accepted

Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol.

Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M, Matsuoka M, Niikura T, Aiso S, Kita Y, Iwatsubo T, Nishimoto I.

J. Neurosci. 23 ( 24 ) 8513 - 8525 2003.09

Research paper (scientific journal), Joint Work, Accepted

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Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins.

Zhu Y, Miwa Y, Yamanaka A, Yoda T, Shibahara M, Abe Y, Sakurai T, Goto K

J. Pharmacol. Sci. 92 ( 3 ) 259 - 266 2003.07

Research paper (scientific journal), Joint Work, Accepted

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Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults

Hashimoto Yuichi, Niikura Takako, Ito Yuko, Sudo Haruka, Hata Michihiro, Arakawa Erika, Abe Yoichiro, Kita Yoshiko, Nishimoto Ikuo

J. Neurosci. 21 ( 23 ) 9235-9245 2001.12

Research paper (scientific journal), Joint Work, Accepted

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Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer’s V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner.

Niikura T, Hashimoto Y, Okamoto T, Abe Y, Yasukawa T, Kawasumi M, Hiraki T, Kita Y, Terashita K, Kouyama K, Nishimoto I

J. Neurosci. 21 ( 6 ) 1902 - 1910 2001.03

Research paper (scientific journal), Joint Work, Accepted

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Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases

Hashimoto Y, Jiang H, Niikura T, Ito Y, Hagiwara A, Umezawa K, Abe Y, Murayama Y, Nishimoto I

J. Neurosci. 20 ( 22 ) 8401-8409 2000.11

Research paper (scientific journal), Joint Work, Accepted

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Functional analysis of five endothelin-B receptor mutations found in human Hirschsprung disease patients.

Abe Y, Sakurai T, Yamada T, Nakamura T, Yanagisawa M, and Goto K

Biochem. Biophys. Res. Commun. 275 524 - 531 2000.09

Research paper (scientific journal), Joint Work, Accepted

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Subtype-specific trafficking of endothelin receptors

Abe Y, Nakayama K, Yamanaka A, Sakurai T, and Goto K

J. Biol. Chem. 275 ( 12 ) 8664 - 8671 2000.03

Research paper (scientific journal), Joint Work, Accepted

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Cloning and characterization of a novel endothelin receptor subtype in the avian class.

Lecoin L, Sakurai T, Ngo M-T, Abe Y, Yanagisawa M, Le Douarin NM

Proc. Natl. Acad. Sci. USA 95 ( 6 ) 3024 - 3029 1998.03

Research paper (scientific journal), Joint Work, Accepted

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Anticoagulant factor protein S inhibits the proliferation of rat astrocytes after injury.

Tomobe YI, Hama H, Sakurai T, Fujimori A, Abe Y, Goto K

Neurosci. Lett. 214 ( 1 ) 57 - 60 1996.09

Research paper (scientific journal), Joint Work, Accepted

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Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors.

Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T Goto K.

Eur. J. Biochem. 228 ( 1 ) 102 - 108 1995.03

Research paper (scientific journal), Joint Work, Accepted

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Endothelin-1 activates mitogen-activated protein kinases through two independent signalling pathways in rat astrocytes.

Kasuya Y, Abe Y, Hama H, Sakurai T, Asada S, Masaki T, Goto K.

Biochem. Biophys. Res. Commun. 204 ( 3 ) 1325 - 1333 1994.12

Research paper (scientific journal), Joint Work, Accepted

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Activin A stimulates mitogenesis in Swiss 3T3 fibroblasts without activation of mitogen-activated protein kinases.

3. Sakurai T, Abe Y, Kasuya Y, Takuwa T, Shiba R, Yamashita T, Endo T, Goto K.

J. Biol. Chem. 269 ( 19 ) 14118 - 14122 1994.06

Research paper (scientific journal), Joint Work, Accepted

Alterations in protein kinase C activity and membrane lipid metabolism in cerebral vasospasm after subarachnoid hemorrhage.

Takuwa Y, Matsui T, Abe Y, Nagafuji T, Yamashita K, Asano T

J. Cereb. Blood Flow Metab. 13 ( 3 ) 409 - 415 1993.06

Research paper (scientific journal), Joint Work, Accepted

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Endothelin-1-induced phosphorylation of the 20-kDa myosin light chain and caldesmon in porcine coronary artery smooth muscle.

Abe Y, Kasuya Y, Kudo M, Yamashita K, Goto K, Masaki T, and Takuwa Y

Jpn. J. Pharmacol. 57 ( 3 ) 431 - 435 1991.12

Research paper (scientific journal), Joint Work, Accepted

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