Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles
Ehsan Dadgostar1,2, Vida Tajiknia3, Negar Shamsaki4, Mojtaba Naderi-Taheri5, Michael Aschner6, Hamed Mirzaei7, Omid Reza Tamtaji5,71Department of Psychiatry, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
3Department of Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
4Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
5Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
6Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
7Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
EXCLI J 2021;20:Doc983
Brain-related disorders are leading global health problems. Various internal and external factors are involved in the progression of brain-related disorders. Inflammatory pathways, oxidative stresses, apoptosis, and deregulations of various channels are critical players in brain-related disorder pathogenesis. Among these players, aquaporins (AQP) have critical roles in various physiological and pathological conditions. AQPs are water channel molecules that permit water to cross the hydrophobic lipid bilayers of cellular membranes. AQP4 is one of the important members of AQP family. AQPs are involved in controlling apoptosis pathways in brain-related disorders. In this regard, several reports have evaluated the pathological effects of AQP4 by targeting the apoptosis-related processes in brain-related disorders. Here, for the first time, we highlight the impact of AQP4 on apoptosis-related processes in brain-related disorders.
Keywords: Aquaporin 4, apoptosis, brain diseases
Brain-related disorders represent significant health problems (Olesen et al., 2012). The multifactorial pathophysiology of brain-related disorders has yet to be fully understood. Shedding further light on their mechanisms may improve treatments, affording new targets for pharmacological interventions. Several clinical risk factors have been recognized, and multiple cellular and molecular pathways and targets have been hypothesized as triggers of brain related disorders (Hughes et al., 2012), such as inflammation, apoptosis, and aquaporins (AQPs), to name a few (Kouchaki et al., 2017, 2018; Shah et al., 2003; Tamtaji et al., 2019).
The apoptotic pathways have essential roles in the pathophysiology of brain-related disorders. Apoptosis is an orderly autonomous death process controlled by several genes (Peter, 2011), aimed at removing dying cells and avoid tissue damage (Ravichandran, 2011). In recent years, apoptosis has been evaluated as a therapeutic target for different neurological disorders such as Alzheimer's disease, stroke (Alam, 2003; Sheng et al., 2009), and brain tumors, such as gliomas (Iwamaru et al., 2007). Various cellular and molecular mechanisms are associated with apoptosis in brain-related disorders, with channels and cell transmitters (e.g., aquaporin 4) playing significant roles in regulating apoptosis (Jablonski et al., 2007; Tamtaji et al., 2019).
Aquaporins are water channel proteins (Preston et al., 1992). Structurally, AQPs are composed of eight membrane-embedded domains, of which six are membrane-spanning and their N- and C-termini are in the cytoplasm (Ho et al., 2009). AQP4 are involved in the pathophysiology of brain-related disorders (Lee et al., 2012; Xu et al., 2015), as for example, in spontaneous recurrent seizure in AQP4-deficient mice (Lee et al., 2012). Further, AQP4 deficiency has been shown to exacerbate cognitive disorders and Aβ aggregation in an animal model of AD (Xu et al., 2015), as well as other brain-related disorders (Chu et al., 2014; Ding et al., 2013). Chu et al. (2014) reported that AQP4 deletion increased the rate of apoptosis after intracerebral hemorrhage in mice. This effect was mediated by increased cytokine expression, such as TNF-α and IL-1β, which initiated the apoptotic cascade and activated caspase-3 and -8. Another study has shown that IL-6 mediated the increase in apoptosis induced by interferon-α, likely by the down-regulation of AQP4 in human hippocampal progenitor cell line HPC0A07/03C (Borsini et al., 2017).
Several studies have evaluated the relationship between AQP4 and the pathophysiology of brain-related disorders (Lee et al., 2012; Xu et al., 2015). Given the reported role of AQP4 in controlling apoptotic pathways (Zheng et al., 2017; Chu et al., 2014), this novel review addresses current knowledge on the relationship between AQP4 and apoptosis in brain-related disorders.
Mechanisms Associated with Apoptosis
There are two main apoptotic signaling pathways (the extrinsic and intrinsic pathways), mutually affecting each other (Figure 1(Fig. 1)) (Igney and Krammer, 2002). The extrinsic pathway begins in the cell surface where various ligands and death-related receptors are located (Puviani et al., 2003; Lan et al., 2011; Wang et al., 2008). Tumor necrosis factor α (TNF-α) is a member of the TNF superfamily of ligands; it is a pro-inflammatory cytokine that has an important role in the pathophysiology of several diseases (Victor and Gottlieb, 2002). The extrinsic signaling pathway begins with transmembrane receptor-mediated interactions through the TNF receptor gene superfamily; it has a cysteine-rich extracellular domain and a cytoplasmic domain composed of 80 amino acids. The cytoplasmic or death domain transmit signals related to cell death from the cell surface to the intracellular signaling pathways (Ashkenazi, 2002; Wang and El-Deiry, 2003; Wiens and Glenney, 2011). Interaction of TNFR1-associated death domain protein (TRADD), a 34 kDa protein with TNFR1, occurs following TNF binding to TNFR1 (Hsu et al., 1995). In addition, FAS (CD95) and FASL ligand (CD95L), as well as CD40 and membrane-bound CD40L, have essential roles in the extrinsic apoptosis signaling pathway (Walczak and Krammer, 2000; Rudi et al., 1998).
The intrinsic signaling pathway initiates apoptosis via non-receptor-mediated stimulation that is activating intracellular signals that influence targets within the cell, particularly in the mitochondria. The intrinsic pathway is regulated by B-cell lymphoma protein 2 (Bcl2) family proteins causing the release of cytochrome c from mitochondria leading to activation of caspase-9 through cytosolic apoptosome complex formation with apoptotic protease activating factor-1 (Apaf-1) (Shakeri et al., 2017). In turn, caspase-9 leads to activation of caspase-3/6/7 and DNA fragmentation (Slee et al., 2001; Porter and Janicke, 1999). In addition, different proteins, including Bcl2 family proteins like Bax/Bak, induce mitochondrial membrane permeabilization, leading to the release of pro-apoptotic proteins from the mitochondria (Ruffolo et al., 2000; Newmeyer and Ferguson-Miller, 2003; Schuler and Green, 2001; Gross, 2016). These pro-apoptotic proteins such as apoptosis inducing factor (AIF), Caspase-Activated DNAse (CAD) and (Smac)/DIABLO and HtrA2/Omi leads to DNA fragmentation (Hong et al., 2004; Joza et al., 2001; Li et al., 2001; Fulda, 2015).
In humans, two main isoforms of AQP4, including M1 (known as a long isoform) and M23 (known as short isoform) exist. The two isoforms are generated by alternative splicing. M1 translation begins at Met-1, and for M23, translation begins at Met-23 (Yang et al., 1995; Lu et al., 1996), Orthogonal arrays of particles (OAPs) are supramolecular crystalline assemblies formed by the aggregation of AQP4 tetramers (Verkman et al., 2013). AQP4 protein is located in glial cells, ventricles, blood vessels, subfornical organ, and supraoptic nucleus (Nielsen et al., 1997; Satoh et al., 2007). In astrocytes, AQP4 is expressed in the end-feet surrounding blood vessels (Hubbard et al., 2015). In addition, AQP4 is colocalized with the proteoglycan brevican, which is expressed in cerebellar astrocytes (Hubbard et al., 2015). Notably, when water enters via the lamellipodium into the cytoplasm driven by an osmotic gradient, astrocyte migration can be enhanced by AQP4. AQP4 has also a crucial function in the neuroexcitation, secondary to neuronal release of isoosmolar K+, followed by its uptake and water by astrocytes on the other side of the synaptic cleft (Papadopoulos and Verkman, 2013). AQP4 has different functional roles, such as regulation of body water balance and water flow and the K+ reuptake. Astrocytes in AQP4−/− mice show enhanced tracer coupling, leading to improvement in the re-distribution of [K+]o in the hippocampus (Strohschein et al., 2011). Deletion of astrocytic connexins triggers down-regulation of AQP4 expression and a reduction of perivascular AQP4 (Katoozi et al., 2020). The expression profiles of AQP4 have confirmed this protein facilitates the movement of water between brain and blood and also between cerebrospinal fluid (CSF) and the brain parenchyma (Solenov et al., 2004). AQP4 is vital for the maintenance of blood-brain barrier integrity (Zhou et al., 2008), and it accelerates neuronal activity and astrocyte migration in brain (Tait et al., 2008). High-mobility group box 1 indirectly up-regulates AQP4 expression microglia-astrocyte interaction (Ohnishi et al., 2014). Figure 2(Fig. 2) (Reference in Figure 2: Verkman, 2011) illustrates structure and function of AQPs.
AQP4 Deficiency and Apoptosis in the Brain-Related Disorders
Alzheimer's disease (AD) is a leading cause of dementia (Prince et al., 2013). Extracellular accumulation of amyloid β (Aβ) peptides and hyper-phosphorylation of tau proteins play an important role in the pathogenesis of AD (Grundke-Iqbal et al., 1986; Dronse et al., 2017). In vitro studies have shown that Aβ induces neuronal apoptosis (Estus et al., 1997; Josepha et al., 2001; Kienlen-Campard et al., 2002), and that the c-Jun N-terminal kinases (JNK)-Fas ligand-Fas pathway mediates Aβ-induced apoptosis (Morishima et al., 2001). Aβ significantly decreases the expression of Bcl and elevates Smac release and activation of JNK (Yao et al., 2005). In addition to reducing the expression of Bcl-2, Aβ increases Bax expression (Paradis et al., 1996).
AQP4 mediates synaptic plasticity and spatial memory processes (Scharfman and Binder, 2013). AQP4 expression is linked to astrocytic pathology and amyloid deposition in transgenic murine models of AD (Yang et al., 2017). Furthermore, AQP4 redistribution facilitates the formation of reactive glial and astrocyte structural plasticity and decreases neuropathology in mouse models of AD (Smith et al., 2019). AQP4 deficiency exacerbates memory deficits and brain oxidative stress (Liu et al., 2012), and polymorphisms in AQP4 are predictive of amyloid burden and disease stage progression. For example, the AQP4 SNP rs151244 is associated with increased Aβ deposition (Chandra et al., 2021).
AQP4 knockdown has been shown to decrease Aβ(1-42)-induced apoptosis and activation in cultured astrocytes, which was related to a diminished uptake of Aβ secondary to decreased up-regulation of low-density lipoprotein receptor-related protein-1 (Yang et al., 2012). In human hippocampal progenitor cell line, HPC0A07/03C, IL-6 has been shown to mediate increased apoptosis induced by interferon-α, potentially via down-regulation of AQP4 (Borsini et al., 2017). Figure 3(Fig. 3) (Reference in Figure 3: Semmler et al., 2020) illustrates molecular mechanisms involved in the effect of reactive oxygen and nitrogen species (RONS) via AQs.
Cerebral ischemic disease, a common form of stroke, remains one of the leading causes of morbidity and mortality worldwide (Virani et al., 2020). Ischemia increases caspase-3 expression and neuronal apoptosis (Deng et al., 2019). Bcl-xL has a neuroprotective effect against brain ischemia (Cao et al., 2002). Elevation of AIF, cytochrome c and Smac/DIABLO is also inherent to cerebral ischemia (Kratimenos et al., 2017).
In mice, AQP4 deficiency manifests with astrocytic dysfunction after focal cerebral ischemia (Shi et al., 2012). AQP4 has been implicated in cerebral water transport and the formation or resorption of edema fluid from the brain parenchyma (Bloch and Manley, 2007). Manley et al. (2000) have shown that AQP4-deficient mice had better neurological outcome and attenuated brain edema after focal ischemic stroke. AQP4 deficiency exacerbated ischemia/reperfusion injury with an increase in infarct size, loss of CA1 neurons, and hypertrophy of astrocytes in mice (Zeng et al., 2012). In addition AQP4-deficient mice displayed greater neuronal loss and microglial activation, concomitant with increased neutrophil infiltration in the brain after focal cerebral ischemia (Shi et al., 2012). Pretreatment with TGN-020, an AQP4 inhibitor, markedly reduced brain edema and the size of cortical infarction in a model of brain ischemia (Igarashi et al., 2011).
Several studies have demonstrated that AQP4 expression directly correlates with apoptosis activation. Zheng et al. (2017) reported that overexpression of miR-145 inhibited apoptosis via AQP4 in a cerebral ischemic stroke model. Another study reported that AQP4 deficiency significantly reduced cell apoptosis and increased astrocytic health in cerebral ischemic stroke (Zheng et al., 2017). Pirici et al. (2018) reported lower number of caspase-3-positive cells following administration of TGN-020, an inhibitor of AQP4 in an animal model of ischemic stroke.
Intracerebral hemorrhage (ICH) is known as the most common hematoma stroke sub-type. Clinical presentation is diverse according to the location and size of hematoma and intraventricular extension of hemorrhage (An et al., 2017). Apoptotic pathways have an important role in ICH, associated with caspase-3 and Bcl-2 family expression changes (Chang et al., 2014; Sun et al., 2017).
AQP4 SNP rs1054827 has been shown to be associated with ICH and increased perihematomaloedema volume (Appelboom et al., 2015). AQP4 deletion elevates intracerebral hemorrhage damage, including neuronal death/TUNEL-positive cells, blood-brain barrier damage, and edema formation (Tang et al., 2010). VEGF has been shown to decrease brain edema and neuronal death after ICH, likely related to up-regulation of AQP4 via ERK and JNK pathway activation (Chu et al., 2013). Erythropoietin (EPO) has been shown to protect the blood-brain barrier integrity upon ICH concomitant with AQP4 activation secondary to p38-MAPK and JNK binding to the EPO receptor (Chu et al., 2014). In addition, curcumin, a flavonoid, significantly reduced brain edema in an animal model of ICH by reducing AQP4 expression (Wang et al., 2015).
In addition, a reverse correlation between AQP4 and activation of apoptotic pathway has been reported. Chu et al. (2014) reported that AQP4 deletion elevated apoptosis after ICH in mice, and that the underlying mechanism was mediated by several cytokines, such as TNF-α and IL-1β, which, in turn, initiated the apoptotic cascade and activated caspase-3 and -8.
Gliomas are one of the most common tumors of the CNS. Patients suffering from malignant gliomas are rarely prognosed, limiting efficient and timely treatments, and by inference, cure (Castro et al., 2003). In glioma, Bcl-2 levels are increased, and apoptosis is decreased via suppression of caspase-3 and -7 signaling (Stegh et al., 2008). In addition, Fas, FasL and caspases-8 are inhibited in tumor glioma cells (Saggioro et al., 2014). Unlike other brain-related disorders, apoptosis induction has been advanced as a treatment strategy for glioma (Ehtesham et al., 2002).
AQP-4 mRNA expression is decreased in tumor specimens of glioblastoma patients without seizures (Isoardo et al., 2012). AQP4 is involved in cell migration and invasion of glioblastoma (Ding et al., 2011). It has been posited that connexin 43 (Cx43) is a downstream effector for AQP4, although, AQP4 and Cx43 operate via two distinct mechanisms in triggering brain edema in the course of gliomas (Li et al., 2015). The redistribution of AQP4 in glioma cells is a reaction to vascular endothelial growth factor (VEGF)-induced vasogenic edema for facilitating the reabsorption of excess fluid (Yang et al., 2012). Overexpression of miRNA-320a leads to the inhibition of cell migration and invasion by targeting AQP4 (Xiong et al., 2018). Glioma radiotherapy and chemotherapy have been shown to down-regulate AQP4 expression in tumor sample, contributing to resolution of brain edema (Nico et al., 2009). Temozolomide (TMZ), an effective drug for glioma, has been shown to control invasion and proliferation of malignant glioma by inhibiting AQP4 expression secondary to the activation of p38 signaling in glioma cell lines (Chen et al., 2017). Thus, induction of apoptosis may represent a therapeutic strategy for the treatment of glioma (Ding et al., 2013).
Increasing evidence has indicated that AQP4 has a dual role in the control of apoptosis signaling in brain-related disorders. In the present review, we summarized the relationship between AQP4 and apoptosis in brain-related disorders, including AD, cerebral ischemic stroke, intracerebral hemorrhage, and glioma (Figure 1(Fig. 1)). Taken together, AQP4 is a mediator of brain pathogenesis, exerting its effects by targeting apoptosis-related processes. Future assessments on the relationship between AQP4 and apoptosis are required in hope of establishing a novel target for pharmacological approaches in the treatment of glioma and other CNS disorders.
Hamed Mirzaei and Omid Reza Tamtaji (Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran; E-mail: email@example.com) contributed equally as corresponding authors.
The authors declare no conflict of interest.
No specific source of funding is associated with this work.
HM, ED, MA, MN-T and O-RT contributed in the conception or design of the work and drafting of the manuscript. All authors confirmed the final version for submission.
1. Alam JJ. Apoptosis: Target for novel drugs. Trends Biotechnol. 2003;21:479-83.
2. An SJ, Kim TJ, Yoon B-W. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017;19(1):3-10.
3. Appelboom G, Bruce S, Duren A, Piazza M, Monahan A, Christophe B, et al. Aquaporin-4 gene variant independently associated with oedema after intracerebral haemorrhage. Neurol Res. 2015;37:657-61.
4. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2(6):420-30.
5. Bloch O, Manley GT. The role of aquaporin-4 in cerebral water transport and edema. Neurosurg Focus. 2007;22(5):E3.
6. Borsini A, Cattaneo A, Malpighi C, Thuret S, Harrison NA;MRC ImmunoPsychiatry Consortium, et al. Interferon-alpha reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms. Int J Neuropsychopharmacol. 2017;21:187-200.
7. Cao G, Pei W, Ge H, Liang Q, Luo Y, Sharp FR, et al. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci. 2002;22:5423-31.
8. Castro MG, Cowen R, Williamson IK, David A, Jimenez-Dalmaroni MJ, Yuan X, et al. Current and future strategies for the treatment of malignant brain tumors. Pharmacol Ther. 2003;98:71-108.
9. Chandra A, Farrell C, Wilson H, Dervenoulas G, De Natale ER, Politis M, et al. Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum. Neurobiol Aging. 2021;97:1-9.
10. Chang P, Dong W, Zhang M, Wang Z, Wang Y, Wang T, et al. Anti-necroptosis chemical necrostatin-1 can also suppress apoptotic and autophagic pathway to exert neuroprotective effect in mice intracerebral hemorrhage model. J Mol Neurosci. 2014;52:242-9.
11. Chen Y, Gao F, Jiang R, Liu H, Hou J, Yi Y, et al. Down‐regulation of AQP4 expression via p38 MAPK signaling in temozolomide-induced glioma cells growth inhibition and invasion impairment. J Cell Biochem. 2017;118:4905-13.
12. Chu H, Ding H, Tang Y, Dong Q. Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4. Lab Invest. 2014;94:1042-53.
13. Chu H, Tang Y, Dong Q. Protection of vascular endothelial growth factor to brain edema following intracerebral hemorrhage and its involved mechanisms: Effect of aquaporin-4. PloS One. 2013;8(6):e66051.
14. Chu H, Xiang J, Wu P, Su J, Ding H, Tang Y, et al. The role of aquaporin 4 in apoptosis after intracerebral hemorrhage. J Neuroinflamm. 2014;11(1):184.
15. Deng C, Li J, Li L, Sun F, Xie J. Effects of hypoxia ischemia on caspase-3 expression and neuronal apoptosis in the brain of neonatal mice. Exp Ther Med. 2019;17:4517-21.
16. Ding T, Ma Y, Li W, Liu X, Ying G, Fu L, et al. Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells. Int J Oncol. 2011;38:1521-31.
17. Ding T, Zhou Y, Sun K, Jiang W, Li W, Liu X, et al. Knockdown a water channel protein, aquaporin-4, induced glioblastoma cell apoptosis. PloS One. 2013;8 (8):e66751.
18. Dronse J, Fliessbach K, Bischof GN, von Reutern B, Faber J, Hammes J,et al. In vivo patterns of tau pathology, amyloid-beta burden, and neuronal dysfunction in clinical variants of Alzheimer's disease. J Alzheimer's Dis. 2017;55:465-71.
19. Ehtesham M, Kabos P, Gutierrez MA, Chung NH, Griffith TS, Black KL, et al. Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2002;62:7170-4.
20. Estus S, Tucker HM, Van Rooyen C, Wright S, Brigham EF, Wogulis M, et al. Aggregated amyloid-β protein induces cortical neuronal apoptosis and concomitant “apoptotic” pattern of gene induction. J Neurosci. 1997;17:7736-45.
21. Fulda S. Smac mimetics as IAP antagonists. Semin Cell Dev Biol. 2015;39:132-8.
22. Gross A. BCL-2 family proteins as regulators of mitochondria metabolism. Biochim Biophys Acta. 2016;1857:1243-6.
23. Grundke-Iqbal I, Iqbal K, Tung Y-C, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913-7.
24. Ho JD, Yeh R, Sandstrom A, Chorny I, Harries WE, Robbins RA, et al. Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance. Proc Natl Acad Sci U S A. 2009;106:7437-42.
25. Hong SJ, Dawson TM, Dawson VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci. 2004;25:259-64.
26. Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell. 1995;81:495-504.
27. Hubbard JA, Hsu MS, Seldin MM, Binder DK. Expression of the astrocyte water channel aquaporin-4 in the mouse brain. ASN Neuro. 2015;7(5):1759091415605486.
28. Hughes CG, Patel MB, Pandharipande PP. Pathophysiology of acute brain dysfunction: What's the cause of all this confusion? Curr Opin Crit Care. 2012;18:518-26.
29. Igarashi H, Huber VJ, Tsujita M, Nakada T. Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. Neurol Sci. 2011;32:113-6.
30. Igney FH, Krammer PH. Death and anti-death: Tumour resistance to apoptosis. Nat Rev Cancer. 2002;2:277-88.
31. Isoardo G, Morra I, Chiarle G, Audrito V, Deaglio S, Melcarne A, et al. Different aquaporin-4 expression in glioblastoma multiforme patients with and without seizures. Mol Med. 2012;18:1147-51.
32. Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007;26:2435-44.
33. Jablonski EM, Mattocks MA, Sokolov E, Koniaris LG, Hughes Jr FM, Fausto N, et al. Decreased aquaporin expression leads to increased resistance to apoptosis in hepatocellular carcinoma. Cancer Lett. 2007;250:36-46.
34. Josepha J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA. Copernicus revisited: Amyloid beta in Alzheimer’s disease. Neurobiol Aging. 2001;22:131-46.
35. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature. 2001;410(6828):549-54.
36. Katoozi S, Skauli N, Zahl S, Deshpande T, Ezan P, Palazzo C, et al. Uncoupling of the astrocyte syncytium differentially affects AQP4 isoforms. Cells. 2020;9 (2):382.
37. Kienlen-Campard P, Miolet S, Tasiaux B, Octave J-N. Intracellular amyloid-β1-42, but not extracellular soluble amyloid-β peptides, induces neuronal apoptosis. J Biol Chem. 2002;277:15666-70.
38. Kouchaki E, Kakhaki RD, Tamtaji OR, Dadgostar E, Behnam M, Nikoueinejad H, et al. Increased serum levels of TNF-α and decreased serum levels of IL-27 in patients with Parkinson disease and their correlation with disease severity. Clin Neurol Neurosurg. 2018;166:76-9.
39. Kouchaki E, Tamtaji OR, Dadgostar E, Karami M, Nikoueinejad H, Akbari H. Correlation of serum levels of IL-33, IL-37, soluble form of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), and circulatory frequency of VEGFR2-expressing cells with multiple sclerosis severity. Iran J Allergy Asthma Immunol. 2017;16:329-37.
40. Kratimenos P, Koutroulis I, Agarwal B, Theocharis S, Delivoria-Papadopoulos M. Effect of Src kinase inhibition on cytochrome C, Smac/DIABLO and Apoptosis Inducing Factor (AIF) following cerebral hypoxia-ischemia in newborn piglets. Sci Rep. 2017;7(1):16664.
41. Lan Y-H, Wu Y-C, Wu K-W, Chung J-G, Lu C-C, Chen Y-L, et al. Death receptor 5-mediated TNFR family signaling pathways modulate γ-humulene-induced apoptosis in human colorectal cancer HT29 cells. Oncol Rep. 2011;25:419-24.
42. Lee DJ, Hsu MS, Seldin MM, Arellano JL, Binder DK. Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis. Exp Neurol. 2012;235:246-55.
43. Li G, Liu X, Liu Z, Su Z. Interactions of connexin 43 and aquaporin-4 in the formation of glioma-induced brain edema. Mol Med Rep. 2015;11:1188-94.
44. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001;412(6842):95-9.
45. Liu L, Lu Y, Kong H, Li L, Marshall C, Xiao M, et al. Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and D-galactose injection. Int J Neuropsychopharmacol. 2012;15:55-68.
46. Lu M, Lee MD, Smith BL, Jung JS, Agre P, Verdijk M, et al. The human AQP4 gene: definition of the locus encoding two water channel polypeptides in brain. Proc Natl Acad Sci U S A. 1996;93:10908-12.
47. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6(2):159-63.
48. Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, et al. β-Amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci. 2001;21:7551-60.
49. Newmeyer DD, Ferguson-Miller S. Mitochondria: Releasing power for life and unleashing the machineries of death. Cell. 2003;112:481-90.
50. Nico B, Mangieri D, Tamma R, Longo V, Annese T, Crivellato E, et al. Aquaporin-4 contributes to the resolution of peritumoural brain oedema in human glioblastoma multiforme after combined chemotherapy and radiotherapy. Eur J Cancer. 2009;45:3315-25.
51. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells: High-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997;17:171-80.
52. Ohnishi M, Monda A, Takemoto R, Fujimoto Y, Sugitani M, Iwamura T, et al. High-mobility group box 1 up-regulates aquaporin 4 expression via microglia–astrocyte interaction. Neurochem Int. 2014;75:32-8.
53. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B, Group CS, et al. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19:155-62.
54. Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013;14:265-77.
55. Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A. Amyloid β peptide of Alzheimer’s disease downregulates Bcl-2 and upregulates Bax expression in human neurons. J Neurosci. 1996;16:7533-9.
56. Peter ME. Apoptosis meets necrosis. Nature. 2011;471 (7338):310-2.
57. Pirici I, Balsanu T, Bogdan C, Margaritescu C, Divan T, Vitalie V, et al. Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways. Int J Mol Sci. 2018;19(1):46.
58. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99-104.
59. Preston GM, Carroll TP, Guggino WB, Agre P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science. 1992;256 (5055):385-7.
60. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimer's & Dementia. 2013;9(1):63-75.e62.
61. Puviani M, Marconi A, Pincelli C, Cozzani E. Fas ligand in pemphigus sera induces keratinocyte apoptosis through the activation of caspase-8. J Invest Dermatol. 2003;120:164-7.
62. Ravichandran KS. Beginnings of a good apoptotic meal: The find-me and eat-me signaling pathways. Immunity. 2011;35:445-55.
63. Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, Krammer PH, et al. Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest. 1998;102:1506-14.
64. Ruffolo SC, Breckenridge DG, Nguyen M, Goping IS, Gross A, Korsmeyer SJ, et al. BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ. 2000;7:1101-8.
65. Saggioro FP, Neder L, Stávale JN, Paixão-Becker ANP, Malheiros SM, Soares FA, et al. Fas, FasL, and cleaved caspases 8 and 3 in glioblastomas: a tissue microarray-based study. Pathol-Res Pract. 2014;210:267-73.
66. Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H. Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology. 2007;27:245-56.
67. Scharfman HE, Binder DK. Aquaporin-4 water channels and synaptic plasticity in the hippocampus. Neurochem Int. 2013;63:702-11.
68. Schuler M, Green DR. Mechanisms of p53-dependent apoptosis. Biochem Soc Trans. 2001;29:684-8.
69. Semmler ML, Bekeschus S, Schäfer M, Bernhardt T, Fischer T, Witzke K, et al. Molecular mechanisms of the efficacy of cold atmospheric pressure plasma (CAP) in cancer treatment. Cancers (Basel). 2020;12 (2):269.
70. Shah K, Tang Y, Breakefield X, Weissleder R. Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo. Oncogene. 2003;22(44):6865.
71. Shakeri R, Kheirollahi A, Davoodi J. Apaf-1: Regulation and function in cell death. Biochimie. 2017;135:111-25.
72. Sheng B, Gong K, Niu Y, Liu L, Yan Y, Lu G, et al. Inhibition of γ-secretase activity reduces Aβ production, reduces oxidative stress, increases mitochondrial activity and leads to reduced vulnerability to apoptosis: Implications for the treatment of Alzheimer's disease. Free Rad Biol Med. 2009;46:1362-75.
73. Shi W-Z, Qi L-L, Fang S-H, Lu Y-B, Zhang W-P, Wei E-Q. Aggravated chronic brain injury after focal cerebral ischemia in aquaporin-4-deficient mice. Neurosci Lett. 2012;520:121-5.
74. Shi W-Z, Zhao C-Z, Zhao B, Shi Q-J, Zhang L-H, Wang Y-F, et al. Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice. Neurosci Bull. 2012;28:680-92.
75. Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 2001;276:7320-6.
76. Smith AJ, Duan T, Verkman AS. Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer's disease by remodeling peri-plaque astrocyte structure. Acta Neuropathol Commun. 2019;7(1):74.
77. Solenov E, Watanabe H, Manley GT, Verkman A. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am J Physiol Cell Physiol. 2004;286:C426-32.
78. Stegh AH, Kesari S, Mahoney JE, Jenq HT, Forloney KL, Protopopov A, et al. Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci U S A. 2008;105:10703-8.
79. Strohschein S, Hüttmann K, Gabriel S, Binder DK, Heinemann U, Steinhäuser C. Impact of aquaporin‐4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia. 2011;59:973-80.
80. Sun DB, Xu MJ, Chen QM, Hu HT. Significant elevation of serum caspase-3 levels in patients with intracerebral hemorrhage. Clin Chim Acta. 2017;471:62-7.
81. Tait MJ, Saadoun S, Bell BA, Papadopoulos MC. Water movements in the brain: role of aquaporins. Trends Neurosci. 2008;31:37-43.
82. Tamtaji OR, Behnam M, Pourattar MA, Jafarpour H, Asemi Z. Aquaporin 4: A key player in Parkinson's disease. J Cell Physiol. 2019;234:21471-8.
83. Tang Y, Wu P, Su J, Xiang J, Cai D, Dong Q. Effects of Aquaporin-4 on edema formation following intracerebral hemorrhage. Exp Neurol. 2010;223:485-95.
84. Verkman A, Phuan PW, Asavapanumas N, Tradtrantip L. Biology of AQP4 and anti‐AQP4 antibody: Therapeutic implications for NMO. Brain Pathol. 2013;23:684-95.
85. Verkman AS. Aquaporins at a glance. J Cell Sci. 2011;124:2107-12.
86. Victor F, Gottlieb A. TNF-alpha and apoptosis: Implications for the pathogenesis and treatment of psoriasis. J Drugs Dermatol. 2002;1:264-75.
87. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics—2020 update: A report from the American Heart Association. Circulation. 2020;141 (9):E139-E596.
88. Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res. 2000;256:58-66.
89. Wang B-f, Cui Z-w, Zhong Z-h, Sun Y-h, Sun Q-f, Yang G-y, et al. Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression. Acta Pharmacol Sin. 2015;36:939-48.
90. Wang L, Du F, Wang X. TNF-α induces two distinct caspase-8 activation pathways. Cell. 2008;133:693-703.
91. Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22 (53):8628.
92. Wiens GD, Glenney GW. Origin and evolution of TNF and TNF receptor superfamilies. Dev Comp Immunol. 2011;35:1324-35.
93. Xiong W, Ran J, Jiang R, Guo P, Shi X, Li H, et al. miRNA-320a inhibits glioma cell invasion and migration by directly targeting aquaporin 4. Oncol Rep. 2018;39:1939-47.
94. Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegen. 2015;10:58.
95. Yang B, Ma T, Verkman A. cDNA cloning, gene organization, and chromosomal localization of a human mercurial insensitive water channel evidence for distinct transcriptional units. J Biol Chem. 1995;270:22907-13.
96. Yang J, Zhang R, Shi C, Mao C, Yang Z, Suo Z, et al. AQP4 association with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of Alzheimer's disease. J Alzheimer's Dis. 2017;57:157-69.
97. Yang L, Wang X, Zhen S, Zhang S, Kang D, Lin Z. Aquaporin-4 upregulated expression in glioma tissue is a reaction to glioma-associated edema induced by vascular endothelial growth factor. Oncol Rep. 2012;28:1633-8.
98. Yang W, Wu Q, Yuan C, Gao J, Xiao M, Gu M, et al. Aquaporin-4 mediates astrocyte response to β-amyloid. Mol Cell Neurosci. 2012;49:406-14.
99. Yao M, Nguyen T-VV, Pike CJ. β-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J Neurosci. 2005;25:1149-58.
100. Zeng XN, Xie LL, Liang R, Sun XL, Fan Y, Hu G. AQP4 knockout aggravates ischemia/reperfusion injury in mice. CNS Neurosci Ther. 2012;18:388-94.
101. Zheng L, Cheng W, Wang X, Yang Z, Zhou X, Pan C. Overexpression of MicroRNA-145 ameliorates astrocyte injury by targeting aquaporin 4 in cerebral ischemic stroke. Biomed Res Int. 2017;2017:9530951.
102. Zheng Y, Wang L, Chen M, Pei A, Xie L, Zhu S. Upregulation of miR-130b protects against cerebral ischemic injury by targeting water channel protein aquaporin 4 (AQP4). Am J Transl Res. 2017;9:3452-61.
103. Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G. Altered blood–brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport. 2008;19(1):1-5.
Figure 1: Apoptosis-associated cellular and molecular pathways
Figure 2: A schema of the role of AQPs. A. AQP monomers composed of helical domains surrounding a narrow aqueous pore. Monomers assemble to form tetramers in the membrane. B. AQP4 facilitates water movement into and out of the brain across brain-fluid barriers at locations indicated. This figure was adapted from Verkman (2011).
Figure 3: A schema of molecular mechanisms involved in the effect of reactive oxygen and nitrogen species (RONS) via Aquaporins (AQ). This figure is adapted from Semmler et al. (2020).