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aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer’s disease

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Neural Regeneration Research 2022年第9期17卷 2079-2088页

作者： Yun Liu Pan-Pan Hu Shuang Zhai Wei-Xi Feng Rui Zhang Qian Li Charles Marshall Ming Xiao Ting Wu Department of Neurology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina Jiangsu Province Key Laboratory of Neurodegeneration Nanjing Medical UniversityNanjingJiangsu ProvinceChina Brain Institute the Affiliated Nanjing Brain Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina College of Health Sciences University of Kentucky Center of Excellence in Rural HealthHazardKYUSA

Regular exercise has been shown to reduce the risk of Alzheimer’s disease(AD).Our previous study showed that the protein aquaporin 4(AQP4),which is specifically expressed on the paravascular processes of astrocytes,is necessary for glymphatic clearance of extracellular amyloid beta(Aβ)from the brain,which can delay the progression of Alzheimer’s disease.However,it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβis involved in beneficial effects of exercise in AD patients.Our results showed that after 2 months of voluntary wheel exercise,APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβburden,glial activation,perivascular AQP4 mislocalization,impaired glymphatic transport,synapse protein loss,and learning and memory defects compared with mice not subjected to the exercise intervention.In contrast,APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ,and the above-mentioned impairments were not alleviated after the 2-month exercise intervention.Compared with age-matched APP/PS1 mice,AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function,Aβplaque deposition,and cognitive impairment,which could not be alleviated after the exercise intervention.These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD.

关键词： Alzheimer’s disease amyloid-beta astrocytes aquaporin-4 glymphatic system learning and memory synaptic protein transgenic mice voluntary exercise

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aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders:progress of experimental models based on disease pathogenesis

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Neural Regeneration Research 2025年第2期20卷 354-365页

作者： Li Xu Huiming Xu Changyong Tang Department of Neurology The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong ProvinceChina

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.

关键词： aquaporin-4 experimental model neuromyelitis optica spectrum disorder pathogenesis

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Relationship Between Hematoma Expansion Induced by Hypertension and Hyperglycemia and Blood-brain Barrier Disruption in Mice and Its Possible Mechanism:Role of aquaporin-4 and Connexin43

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Neuroscience Bulletin 2020年第11期36卷 1369-1380页

作者： Heling Chu Zidan Gao Chuyi Huang Jing Dong Yuping Tang Qiang Dong Department of Neurology Huashan HospitalState Key Laboratory of Medical NeurobiologyFudan UniversityShanghai 200040China Department of Neurology North Huashan HospitalFudan UniversityShanghai 201907China Department of Neurology Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004China Department of Neurology Shanghai East HospitalTongji University School of MedicineShanghai 200120China

We aimed to select an optimized hematoma expansion(HE)model and investigate the possible mechanism of blood-brain barrier(BBB)damage in mice.The results showed that HE occurred in the group with hypertension combined with hyperglycemia(HH-HE)from3 to 72 h after intracerebral hemorrhage;this was accompanied by neurological deficits and hardly influenced the survival rate.The receiver operating characteristic curve suggested the criterion for this model was hematoma volume expansion≥45.0%.Meanwhile,HH-HE aggravated BBB disruption.A protector of the BBB reduced HH-HE,while a BBB disruptor induced a further HH-HE.aquaporin-4(AQP4)knock-out led to larger hematoma volume and more severe BBB disruption.Furthermore,hematoma volume and BBB disruption were reduced by multiple connexin43(Cx43)inhibitors in the wild-type group but not in the AQP4 knock-out group.In conclusion,the optimized HE model is induced by hypertension and hyperglycemia with the criterion of hematoma volume expanding≥45.0%.HH-HE leads to BBB disruption,which is dependent on AQP4 and Cx43.

关键词： Intracerebral hemorrhage Hematoma expansion Animal model Blood-brain barrier aquaporin-4 Connexin43

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aquaporin-4 deficiency attenuates acute lesions but aggravates delayed lesions and microgliosis after cryoinjury to mouse brain

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Neuroscience Bulletin 2012年第1期28卷 61-68页

作者： Wen-Zhen Shi Chun-Zhen Zhao Bing Zhao Xiao-Liang Zheng San-Hua Fang Yun-Bi Lu Wei-Ping Zhang Zhong Chen Er-Qing Wei Department of Pharmacology and Institute of Neurobiology School of Medicine Zhejiang University Hangzhou 310058China

Objective To determine whether aquaporin-4 （AQP4） regulates acute lesions, delayed lesions, and the associated microglial activation after cryoinjury to the brain. Methods Brain cryoinjury was applied to AQP4 knockout （KO） and wild-type mice. At 24 h and on days 7 and 14 after cryoinjury, lesion volume, neuronal loss, and densities of microglia and astrocytes were determined, and their changes were compared between AQP4 KO and wild-type mice. Results Lesion volume and neuronal loss in AQP4 KO mice were milder at 24 h following cryoinjury, but worsened on days 7 and 14, compared to those in wild-type mice. Besides, microglial density increased more, and astrocyte proliferation and glial scar formation were attenuated on days 7 and 14 in AQP4 KO mice. Conclusion AQP4 deficiency ameliorates acute lesions, but worsens delayed lesions, perhaps due to the microgliosis in the late phase.

关键词： aquaporin-4 gene deficiency cryoinjury microglia astrocyte

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Detection of anti-aquaporin-4 autoantibodies in the sera of Chinese neuromyelitis optica patients

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Neural Regeneration Research 2013年第8期8卷 708-713页

作者： Miao Li Weiheng Su Jie Wang Francesco Pisani Antonio Frigeri Tonghui Ma Membrane Channel Research Laboratory Northeast Normal University Department of Neurosurgery China-Japan Union HospitalJilin University National Engineering Laboratory for AIDS Vaccine College of Life ScienceJilin University Department of General and Environmental Physiology and Centre of Excellence in Comparative Genomics (CEGBA) University of Bari

In this study, we recruited 10 neuromyelitis optica patients, two multiple sclerosis patients and two myelitis patients. Chinese hamster lung fibroblast （V79） cells transfected with a human aquaporin-4-mCherry fusion protein gene were used to detect anti-aquaporin-4 antibody in neuromyelitis optica patient sera by immunofluorescence. Anti-aquaporin-4 autoantibody was stably detected by immunofluorescence in neuromyelitis optica patient sera exclusively. The sensitivity of the assay for neuromyelitis optica was 90% and the specificity for neuromyelitis optica was 100%. The anti-aquaporin-4 antibody titers in sera were tested with serial dilutions until the signal disappeared. A positive correlation was detected between Expanded Disability Status Scale scores and serum anti-aquaporin-4 antibody titers. The anti-aquaporin-4 antibody assay is highly sensitive and specific in the sera of Chinese neuromyelitis optica patients. Detection of aquaporin-4 autoantibody is important for the diagnosis and treatment of neuromyelitis optica.

关键词： neural regeneration neurodegenerative diseases neuromyelitis optica multiple sclerosis aquaporin-4 autoimmune disease autoantibody immunofluorescence Expanded Disability StatusScale grants-supported paper photographs-containing paper neuroregeneration

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Reperfusion of the rat brain tissues following acute ischemia： the correlation among diffusion-weighted imaging, histopathology, and aquaporin-4 expression

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Chinese Medical Journal 2011年第19期124卷 3148-3153页

作者： LU Hong HU Hui HE Zhan-ping Department of Radiology Affiliated Haikou Hospital of Xiangya School of Medicine Central South University （Haikou Municipal People＇s Hospital） Haikou Hainan 570208 China

Background Although some studies have reported that aquaporin-4 （AQP4） plays a role in the post-ischemic edema formation and diffusion-weighted imaging （DWI）, little is known about the AQP4 expression in stage of the reperfusion following acute cerebral ischemia, as well as the correlation between histopathology and DWl. The aim of the study was to investigate the correlation among DWl, histopathology and the AQP4 expression in the reperfused rat brain tissues following acute ischemia.Methods Seventy Wistar rats were randomly divided into a control group （group A）, and several occluded and reperfusion groups. They had their middle cerebral artery unilaterally occluded （MCAO） for 30 minutes （group B） followed by 30 minutes （group D） or 60 minutes （group E） of reperfusion, or 60 minutes of MCAO （group C） followed by 30 minutes （group F）, or 60 minutes （group G） of reperfusion （n=10 for each group）. All rats underwent DWl scanning.The relative apparent diffusion coefficient （rADC） value of each rat was calculated. All the rats were sacrificed and the cerebral ischemic tissues were examined for histopathology. Real-time fluro-quantitative polymerase chain reaction （RT-PCR） and Western-blotting were performed. The amount of AQP4 mRNA （Ex △△Ct） and AQP4 protein （Q） was statistically analyzed. The correlation between rADC values and AQP4 mRNA expression was analyzed with the Pearson correlation test.Results In all the reperfusion groups, the areas of hyper-intensity signal in DWl were decreased, and the rADC value increased and the AQP4 expression decreased significantly compared with the occluded group （t=26.89, t=18.26, P〈0.01）. There was a negative correlation between AQP4 mRNA expression and rADC values （r=-0.72, P〈0.01）. A mixed edema, composed of cerebral intracelluar edema and vasogenic brain edema, was observed in all the reperfusion groups.It was more prevalent in groups D and F than in the groups E and G. With the reperfusion time postponed, the cerebral intracelluar edema of the rat was significantly mitigate

关键词： aquaporin-4 magnetic resonance imaging ischemia reperfusion

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重组EGFP-aquaporin-4融合蛋白真核表达载体的构建及其在FRT细胞中的表达和定位

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吉林大学学报（医学版） 2013年第2期39卷 273-277,428页

作者：李凤娥郝峰藏雨轩马睿泽孔繁利刘磊李艳北华大学附属医院神经二科吉林吉林132013 吉林医药学院生物化学检验教研室吉林吉林132013 吉林医药学院基础护理教研室吉林吉林132013 北华大学基础医学院病理生理学教研室吉林吉林132013

目的:构建以增强型绿色荧光蛋白(EGFP)为报告基因的重组真核表达载体pEGFP-aquaporin-4,以EGFP示踪aquaporin-4在Fisher大鼠甲状腺滤泡上皮细胞(FRT细胞)中的表达和定位,为进一步研究aquaporin-4提供实验依据。方法:应用RT-PCR方法获得a... 详细信息

目的:构建以增强型绿色荧光蛋白(EGFP)为报告基因的重组真核表达载体pEGFP-aquaporin-4,以EGFP示踪aquaporin-4在Fisher大鼠甲状腺滤泡上皮细胞(FRT细胞)中的表达和定位,为进一步研究aquaporin-4提供实验依据。方法:应用RT-PCR方法获得aquaporin-4编码区基因,克隆入真核表达载体pEGFP-N1。经酶切和测序鉴定证实为aquaporin-4后,Lipofectamine 2000脂质体转染重组EGFP-aquaporin-4融合蛋白真核表达载体至FRT细胞中,倒置荧光显微镜下观察aquaporin-4在FRT细胞中的表达和分布,并应用Western blotting法检测aquaporin-4蛋白的表达。同时检测转入FRT细胞内钙黄绿素的相对荧光强度以判断FRT细胞水通透性的状况。结果:EcoRⅠ和KpnⅠ双酶切和测序重组载体结果证实目的基因aquaporin-4成功克隆到真核表达载体pEGFP-N1中。荧光显微镜下观察融合EGFP的aquaporin-4主要在FRT细胞膜上表达;Western blotting结果证实脂质体转染重组载体的FRT细胞表达aquaporin-4。转染重组EGFP-aquaporin-4融合蛋白真核表达载体的FRT细胞水通透性显著高于未转染的FRT细胞,其水通透性是未转染FRT细胞的1.65倍。结论:成功构建aquaporin-4真核表达载体,证实其可在FRT细胞中表达,并具有明显的膜蛋白特性和良好水通透性。

关键词： aquaporin-4 转染 FRT细胞载体

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Gene interference regulates aquaporin-4 expression in swollen tissue of rats with cerebral ischemic edema Correlation with variation in apparent diffusion coefficient

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Neural Regeneration Research 2012年第21期7卷 1659-1666页

作者： Hui Hu Hong Lu Zhanping He Xiangjun Han Jing Chen Rong Tu Department of Radiology Affiliated Haikou Hospital of Xiangya School of Medicine Central South University (Haikou Municipal People'sHospital) Haikou 570208 Hainan Province China Department of Radiology Medical College of Hainan Province Haikou 570102 Hainan Province China

To investigate the effects of mRNA interference on aquaporin-4 expression in swollen tissue of rats with ischemic cerebral edema, and diagnose the significance of diffusion-weighted MRI, we injected 5 pL shRNA- aquaporin-4 （control group） or siRNA- aquaporin-4 solution （1：800）（RNA interference group） into the rat right basal ganglia immediately before occlusion of the middle cerebral artery. At 0.25 hours after occlusion of the middle cerebral artery, diffusion-weighted MRI displayed a high signal; within 2 hours, the relative apparent diffusion coefficient decreased markedly, aquaporin-4 expression increased rapidly, and intracellular edema was obviously aggravated; at 4 and 6 hours, the relative apparent diffusion coefficient slowly returned to control levels, aquaporin-4 expression slightly increased, and angioedema was observed. In the RNA interference group, during 0.25- 6 hours after injection of siRNA- aquaporin-4 solution, the relative apparent diffusion coefficient slightly fluctuated and aquaporin-4 expression was upregulated; during 0.5 4 hours, the relative apparent diffusion coefficient was significantly higher, while aquaporin-4 expression was significantly lower when compared with the control group, and intracellular edema was markedly reduced; at 0.25 and 6 hours, the relative apparent diffusion coefficient and aquaporin-4 expression were similar when compared with the control group; obvious angioedema remained at 6 hours. Pearson＇s correlation test results showed that aquaporin-4 expression was negatively correlated with the apparent diffusion coefficient （r = -0.806, P 〈 0.01）. These findings suggest that upregulated aquaporin-4 expression is likely to be the main molecular mechanism of intracellular edema and may be the molecular basis for decreased relative apparent diffusion coefficient. aquaporin-4 gene interference can effectively inhibit the upregulation of aquaporin-4 expression during the stage of intracelfular edema with time-effectiveness. Moreover, diffusion-weighted MRI can accurate

关键词： cerebral ischemic edema magnetic resonance imaging diffusion gene silencing aquaporin-4 mRNA interference neural regeneration

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Ammonia induces upregulation of aquaporin-4 in neocortical astrocytes of rats through the p38 mitogen-activated protein kinase pathway

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Chinese Medical Journal 2010年第14期123卷 1888-1892页

作者： PAN Cai-fei ZHU Sheng-mei ZHENG Yue-ying Department of Anesthesiology First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang 310003 China

Background Astrocyte swelling is an important consequence of hepatic encephalopathy, and aquaporin-4 has been reported to play a vital role in this swelling. Ammonia causes astrocyte swelling and is also known to modulate aquaporin-4 expression in the astrocyte foot processes. The purpose of this study was to explore the mechanism of ammonia-induced aquaporin-4 expression, which has been suggested to involve the p38 mitogen-activated protein kinase pathway. Methods We exposed cultured astrocytes to ammonium chloride, an in vitro model of hepatic encephalopathy. The purity of cultured astrocytes was evaluated by fluorescent glial fibrillary acidic protein labeling; cell morphology was assessed by light microscopy; the expression of aquaporin-4, phospho-p38, and p38 were detected by Western blotting analysis. Statistical analysis was performed by one-way factorial analysis of variance, and the relationship between variables was calculated by linear regression using SPSS version 13.0 program for Windows （SPSS, Chicago, IL, USA）. Results The purity of cultured astrocytes was （96.6±1.4）%. Astrocytes swelled significantly when exposed to 5 mmol/L ammonium chloride for 24 hours as compared to non-exposed astrocytes. Co-treatment with 10 μmol/L SB203580 （an inhibitor of p38） attenuated the degree of ammonium chloride induced astrocyte swelling. Western blotting analysis revealed that the expression levels of phospho-p38 and aquaporin-4 in ammonium chloride treated cells were significantly increased relative to the control group （P 〈0.001）; SB203580 co-treatment inhibited the increased expression of phospho-p38 and aquaporin-4 relative to the ammonium chloride treated group （P=0.002 and P=0.015 respectively）. The phosphorylation of p38 and upregulation of aquaporin-4 were highly correlated （r=0.909）. There were no significant differences in total p38 expression among the groups （P=0.341）. Conclusions Ammonium chloride induced upregulation of aquaporin-4 in astrocytes is regulated by the p38 mitogen-activated protein kinas

关键词： ammonia aquaporin-4 astrocytes phospho-p38 mitogen-activated protein kinases

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Effects of propofol on ammonium chloride-exposed astrocyte morphology and aquaporin-4 expression

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Neural Regeneration Research 2011年第5期6卷 383-387页

作者： Hanjian Chen Caifei Pan Peng Guo Yueying Zheng Shengmei Zhu Department of Anesthesiology First Affiliated Hospital Zhejiang University Medical School Hangzhou 310003 Zhejiang Province China Department of Anesthesiology Shaoxing Central Hospital Shaoxing 312030 Zhejiang Province China

Ammonia induces astrocyte swelling, which is strongly associated with overexpression of aquaporin-4. However, the mechanisms by which ammonia induces astrocyte swelling, and subsequently upregulating aquaporin-4 expression, remain unknown. In the present study, astrocytes were cultured in vitro and exposed to ammonium chloride （NH4CI）, followed by propofol protein kinase C agonist, or antagonist, respectively. Astrocyte morphology was observed by light microscopy, and aquaporin-4 expression was detected by western blot analysis. Results showed that propofol or protein kinase C agonist significantly attenuated the degree of NH4CI-induced astrocyte swelling and inhibited increased aquaporin-4 expression. Propofol treatment inhibited aquaporin-4 overexpression in cultured astrocyte induced by NH4CI; protein kinase C pathway activation is potentially involved.

关键词： ammonium chloride aquaporin-4 astrocytes propofol protein kinase C

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