Review Riluzole: A Therapeutic Strategy In Alzheimer’s .
www.aging-us.comAGING 2020, Vol. 12, No. 3ReviewRiluzole: a therapeutic strategy in Alzheimer’s disease by targeting theWNT/β-catenin pathwayAlexandre Vallée1, Jean-Noël Vallée2,3, Rémy Guillevin1, Yves Lecarpentier41DACTIM-MIS, Laboratory of Mathematics and Applications (LMA), University of Poitiers, CHU de Poitiers, Poitiers,France2CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France3Laboratory of Mathematics and Applications (LMA), University of Poitiers, Poitiers, France4Centre de Recherche Clinique, Grand Hôpital de l’Est Francilien (GHEF), Meaux, FranceCorrespondence to: Alexandre Vallée; email: alexandre.g.vallee@gmail.comKeywords: Riluzole, Alzheimer's disease, WNT pathway, glutamate, oxidative stressReceived: December 11, 2019Accepted: January 27, 2020Published: February 8, 2020Copyright: Vallée et al. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the originalauthor and source are credited.ABSTRACTAlzheimer’s disease (AD) is a neurodegenerative disease, where the etiology remains unclear. AD ischaracterized by amyloid-(Aβ) protein aggregation and neurofibrillary plaques deposits. Oxidative stress andchronic inflammation have been suggested as causes of AD. Glutamatergic pathway dysregulation is also mainlyassociated with AD process. In AD, the canonical WNT/β-catenin pathway is downregulated. Downregulation ofWNT/β-catenin, by activation of GSK-3β-induced Aβ, and inactivation of PI3K/Akt pathway involve oxidativestress in AD. The downregulation of the WNT/β-catenin pathway decreases the activity of EAAT2, theglutamate receptors, and leads to neuronal death. In AD, oxidative stress, neuroinflammation andglutamatergic pathway operate in a vicious circle driven by the dysregulation of the WNT/β-catenin pathway.Riluzole is a glutamate modulator and used as treatment in amyotrophic lateral sclerosis. Recent findings havehighlighted its use in AD and its potential increase power on the WNT pathway. Nevertheless, the mechanismby which Riluzole can operate in AD remains unclear and should be better determine. The focus of our review isto highlight the potential action of Riluzole in AD by targeting the canonical WNT/β-catenin pathway tomodulate glutamatergic pathway, oxidative stress and neuroinflammationINTRODUCTIONAlzheimer’s disease (AD) is one of the majorneurodegenerative disease, but its etiology remainsunclear. AD is marked by two major postmortemhallmarks; amyloid-(Aβ) protein aggregation formed byplaque deposits and tau protein hyperphosphorylationwhich results in neurofibrillary tangles. In AD,the common symptoms are cognitive functiondysregulation, memory loss and neurobehavioralmanifestations [1]. Other cognitive and behavioralsymptoms are poor facial recognition ability, socialwithdrawal, increase in motor agitation and wanderinglikelihood [2, 3]. Aging is the main risk factors of AD[4]. Affected neural circuits in aging and AD are thewww.aging-us.com3095same, and involving glutamatergic pathway, oxidativestress and neuroinflammation [5, 6]. Glutamatergicneurons are vulnerable to damages in AD and in aging[7–9]. Oxidative stress and neuroinflammation areconsidered as mainly underlying causes of AD [10, 11].Increase of oxidative stress can be an early indicationof AD [12, 13]. In AD, the accumulation of Aβprotein leads to the decrease of the WNT/β-cateninpathway [14]. Diminution of β-catenin decreasesphosphatidylinositol 3-kinase (PI3K)-protein kinase B(Akt) (PI3K/Akt) pathway activity [15, 16]. Inhibitionof WNT/β-catenin/PI3K/Akt pathway enhancesoxidative stress in mitochondria of AD cells [17]. Thus,activation of the WNT/β-catenin pathway may be aninteresting therapeutic target for AD [18, 19].AGING
Riluzole is a glutamate modulator and used as treatmentin amyotrophic lateral sclerosis [20]. Moreover, use ofRiluzole is associated with prevention of age-relatedcognitive decline [21]. Riluzole administration can becorrelated with induction of dendritic spines clustering[21] depending on glutamatergic neuronal activity [22,23]. In mutant mouse and rat model of AD, Riluzolecan prevent age-related cognitive decline [21, 24].Moreover, Riluzole is associated with the rescue agerelated gene expression changes in hippocampus of rats[6]. Hippocampus region is responsible for learning andmemory and is one of the regions compromised by ADprogression [25, 26].Nevertheless, the mechanism by which Riluzolecan operate in AD remains unclear and should bebetter determine. The focus of our review is tohighlight the potential action of Riluzole in AD bytargeting the canonical WNT/β-catenin pathway tomodulate glutamatergic pathway, oxidative stress andneuroinflammation.HALLMARKS OF AD: OXIDATIVE STRESSAND NEUROINFLAMMATIONAD manifestations are characterized by senileplaques, due to the extracellular accumulation of theamyloid β (Aβ) protein [27], and neurofibrillarytangles (NFTs), caused by hyperphosphorylated tauaggregation [28].Aβ is produced by the sequential cleavage of theAmyloid Precursor Protein (APP), controlled by theβ-secretase (BACE-1) and complex of gammasecretase [29]. NFTs is formed by the aggregation ofhyperphosphorylated microtubule-associated protein(MAP) tau. Tau is a microtubule-stabilizing proteinmaintaining the structure of neuronal cells and theaxonal transport. In AD, multiple kinasesphosphorylate Tau in an aberrantly manner. Thesekinases are the Glycogen synthase kinase-3β (GSK3β), the cyclin-dependent protein kinase-5 (CDK5),the Dual specificity tyrosine-phosphorylationregulated kinase 1A (DYRK1A), the Calmodulindependent protein kinase II (CAMKII), and theMitogen-activated protein kinases (MAPKs) are thebest known oinflammation correlated with neurotoxicity,oxidative stress and cytokine release, are considered aspossible underlying causes [10, 11]. Aβ and NFTsinvolve neuroinflammation and oxidative damagesresulting in progressive neuronal degeneration.Oxidative stress enhancement can be an indicationof AD [13].www.aging-us.com3096In AD, mitochondrial damages enhance the productionof ROS (reactive oxygen species) but diminish theproduction of ATP [33]. Mitochondrial damages affectcell function by enhancing the release of ROS leadingto cell damage and death. Energy depletion is caused bythe disruption of oxidative phosphorylation [34]. Thus,both the dysregulation of mitochondrial activity andoxidative stress enhancement are responsible todementia and neuronal cell death [35–37].Numerous cellular pathways are altered by Aβ-inducedoxidative stress [38]. Neurotoxic effects are induced byAβ peptide through the enhancement of oxidative stressand damages on the membrane, mitochondrial functionand lipids production [39]. NADPH dehydrogenase(complex I) generates superoxide from oxidativephosphorylation into the mitochondrial respiratorychain [40]. Complex I and complex IV (cytochrome coxidase) deficiencies are initiated by Aβ. Thesedeficiencies lead to ROS generation [41].Mitochondrial-derived ROS correlated with Aβ, areinhibited in resistant relative to sensitive cells. Throughthe diminution of the mitochondrial respiration chain,Aβ-resistant cells are less likely to generate ROS andare mainly resistant to depolarization of themitochondria [17].Amyloid oligomers complex into the lipid bilayer andlead to the peroxidation of lipids, proteins andbiomolecule damages [42]. Membrane alterationgenerated by the accumulation of Aβ are induced by theinflux of Ca2 . This leads to the alteration of thehomeostasis of Ca2 leading to mitochondrialdysregulation and neuronal death. Diminution of theactivity of Glutathione (GSH) is responsible for theincrease of Ca2 release and ROS accumulation [43].Then, ROS accumulation affects DNA transcription,DNA oxidation and the activity of the target proteins[44, 45]. Tau leads to the dysregulation of themitochondrial activity, which dysregulates energyproduction, enhances ROS and nitrogen species (RNS)production [46]. ROS and RNS alters the integrity ofcell membranes to induce failure of synapses [47]. ption and cytokines release, includinginterleukin-1 (IL-1) and tumor necrosis factor-α (TNFα), responsible for neuroinflammation [37]. Aβ-relatedinflammatory compound of the disease is one of themain targets to control AD development [48]. Aβstimulates inflammation leading to damage andneuronal death [49].Numerous studies have shown the link betweenneuroinflammation and oxidative stress [50]. NF- Binduces the production of ROS and RNS leading toneuronal damages [51, 52]. NF- B activates COXX-2AGING
and cytosolic phospholipase A2 which stimulateprostaglandins production leading to oxidative stress[53]. Production of peroxide, through the involvementof iNOS and NF- B pathway, is associated withdysregulation of the glucose metabolism [54]. IL-1 canstimulate GSH production in astrocytes through a NF B dependent pathway [55].Excessive activation of extra-synaptic NMDA receptors[63]and excessive downregulation of synaptic NMDAreceptors [64] lead to increase of Aβ release [65].GLUTAMATERGIC PATHWAY IN ADOxidative stress leads to the loss of cell homeostasis bymitochondrial oxidants overproduction [66]. Thedevelopment of oxidative stress in AD compromisesastrocyte function leading to impairment of glutamatetransport and then increasing excitotoxicity to neurons[67]. Aβ interaction on the membrane of astrocytesinduces calcium changes. Mitochondrial dysregulationin astrocytes is associated with a mitochondrialdepolarization, increased conductance and membranepermeability [68]. The formation of calcium selectivechannels on membrane could be induced by Aβ intoastrocytes generating a change in the conductance [69].Aβ insertion in membrane changes the structure ofmembrane [70]. In AD, astrocytes appear as the primarytarget of Aβ, and oxidative stress enhancement isassociated with the alteration of calcium intracellularsignaling [69]. Astrocytes have a major role in neuronalintegrity. Changes in cytokines and oxidative damagesin astrocytes increase neurotoxicity and vulnerability ofneurons [67]. In parallel a vicious and positive crosstalkis observed between oxidativestressandneuroinflammation. NF- B activation induces thegeneration of prostaglandins and oxidative stress [53]whereas oxidative stress can stimulate in a directfeedback NF- B pathway [50]. Thus, interesting drugsshould consider the modulation of astrocyte activity toreduce both inflammation and oxidative stress.Glutamate is a key excitatory neurotransmitter in theCNS, responsible for fast excitatory neurotransmission.In neurons, glutamate is stored in synaptic vesicles,from where it is released. The release of glutamate leadsto an increase in glutamate concentration in the synapticcleft, which binds the ionotropic glutamate receptors.Glutamate is removed from the synaptic cleft andtransported to astrocytes by glutamate transporters (suchas GLT-1 or excitatory amino acid transporters 1 and 2:EAATs 1 and 2) to prevent overstimulation of theglutamate receptor [56]. Astrocytes clear 90% ofexcess glutamate by EAATs and play a major role in theglutamate/glutamine cycle. Following glutamate uptake,glutamine synthetase (GS) catalyzes the ATP-dependentreaction of glutamate and ammonia into glutamine.Glutamine is released and in turn is taken up by neuronsfor conversion back to glutamate by glutaminase.In a physiological state, in astrocytes, β-cateninactivates the gene expression of EAAT2 and GS [57].This allows the re-uptake of glutamate from thesynaptic cleft by astrocytes through EAAT2. Glutamateis then metabolized by GS.In AD, EAAT2 expression is decreased [58]. The overaccumulation of glutamate in the synaptic cleft leads toexcitotoxicity that impairs glutamate receptors locatedon the post-synaptic side of the cleft. This phenomenonleads to calcium overload, mitochondrial dysfunction,apoptosis and ultimately death of the post-synapticneuron. Cell death is restricted to post-synaptic neurons.The decrease if glutamate transmission is significantlyassociated with neuronal death and loss of synapse [56].Moreover, the downregulation of glutamate transport iscorrelated with the decrease of EAAT2 expression inAD [58].Some animal models of AD have shown the importanceof NMDA receptors (glutamatergic N-methyl-Daspartate) in AD and the affection of glutamatergicsynapses [59, 60].Synaptic dysregulation is one the main mechanisminvolved in AD [28] which is present at early step of ADdevelopment [61]. Moreover, Aβ expression is closelyassociated with glutamatergic pathway expression [62].www.aging-us.com3097OXIDATIVE STRESS,NEUROINFLAMMATION ANDGLUTAMATERGIC PATHWAY IN ADTHECANONICALPATHWAY (FIGURE 1)WNT/β-CATENINThe Wingless/Int (WNT) pathway is a family ofsecreted lipid-modified glycoproteins [71]. Severalsignaling are mediated by this pathway, includingfibrosis and angiogenesis [72–74].During eye development, WNT/β-catenin pathwayactivity is highly mediated. Then, a dysfunction of theWNT/β-catenin pathway leads to several ocularmalformations due to defects in cell fate differentiationand determination [75]. During the development of lens,the WNT/β-catenin pathway is stimulated in theperiocular surface ectoderm and lens epithelium [76,77]. For the retinal development, the WNT/β-cateninpathway is stimulated in the dorsal optic vesicle andthen, participates to the activation of RPE at the opticvesicle step. At this level, WNT/β-catenin pathway isAGING
contained to the peripheral RPE [78]. The retinalvascular initiation is mainly modulated by theexpression of the WNT/β-catenin pathway [75]. In theretinal vascular system, WNT/β-catenin pathway iscontrolled by the erythroblast transformation-specific(ETS) transcription factor Erg. Erg has a major and keyrole in angiogenesis [79]. Erg modulates the WNT/βcatenin pathway by promoting β-catenin stability and byregulating the transcription of Frizzled 4 (FZD4) [79].kinase-3β (GSK-3β). Then, β-catenin accumulation inthe cytosol is observed and translocates to the nucleusto bind T-cell factor/lymphoid enhancer factor(TCF/LEF) co-transcription factors. This nuclear bindallows the transcription of WNT-responsive genes, suchas cyclin D1, c-Myc, PDK1, MCT-1 [83, 84].Stimulation of FZD4/β-catenin signaling needs thepresence of the complex LRP5 /LRP6 [80]. LRP5 has amain role while LRP6 presents a minor role in theretinal vascularization [81, 82]. Disheveled (Dsh) formsa complex with Axin, and this prevents thephosphorylation of β-catenin by glycogen synthaseA destruction complex is composed by tumor suppressoradenomatous polyposis coli (APC), Axin, GSK-3β and βcatenin. Then, phosphorylated β-catenin is destroyedin the proteasome. WNT inhibitors, including DKKsand SFRPs, control the WNT/β-catenin pathwayby preventing its ligand-receptor interactions [85].WNT ligands absence is associated with cytosolic βcatenin phosphorylation by GSK-3β.Figure 1. The canonical WNT/β-catenin pathway. Inactivated WNT: Under physiologic circumstances, the cytoplasmic β-catenin islinked to its destruction complex, consisting of APC, AXIN and GSK-3β. β-catenin is phosphorylated by GSK-3β. Thus, phosphorylated βcatenin is destroyed into the proteasome. Then, cytoplasmic level of β-catenin is kept low in the non-presence of WNT ligands. If β-catenin isnot accumulated in the nucleus, the TCF/LEF complex does not stimulate the target genes. DKK1 inhibits the WNT/β-catenin pathwaythrough the bind to WNT ligands or LRP5/6. Activated WNT: When WNT ligands activate both FZD and LRP5/6, DSH is stimulated andphosphorylated by FZD. Phosphorylated DSH in turn activates AXIN, which comes off β-catenin destruction complex. Thus, β-catenin escapesfrom phosphorylation and then accumulates in the cytoplasm. The accumulated cytosolic β-catenin moves into the nucleus, where itinteracts with TCF/LEF and stimulates the transcription of target genes.www.aging-us.com3098AGING
GSK-3β, a neuron-specific intracellular serine-threoninekinase, is the major inhibitor of the WNT pathway [86].GSK-3β regulates numerous pathophysiologicalpathways (cell membrane signaling, neuronal polarityand inflammation) [87–89]. GSK-3β downregulates βcatenin cytosolic accumulation and then its nucleartranslocation [87]. GSK-3β diminishes β-catenin,mTOR (PI3K/Akt pathway downstream), and HIF-1αexpression [90].THECANONICALPATHWAY IN ADWNT/β-CATENINSome evidence has presented a down-regulation of theWnt/β-catenin pathway in the pathogenesis of AD [5, 47,91–94]. Aβ leads to a dysregulation of the WNT/β-cateninpathway in AD [95, 96]. Aβ increases Dickkopf-1(DKK1) expression, a WNT inhibitor. In AD, DKK-1links LRP 5/6, inhibits the complex WNT /Frd anddownregulates the interaction with WNT ligands [97].DKK-1 overexpression has been shown in AD brain ofhumans and transgenic mice [98]. GSK-3β activity isincreased in the hippocampus of AD patients [99]. In AD,GSK-3β phosphorylates MAP tau to enhance NFTsexpression [100–102]. GSK-3β over-activity is associatedin AD with the diminution of β-catenin level and theincrease of tau phosphorylation and NFTs formation[103]. GSK-3β activation enhances the APP cleavage[104]. The inhibition of GSK-3β activity is associatedwith the reversion of cell damages in AD [105].WNT/β-CATENIN AND GLUTAMATERGICPATHWAY (FIGURE 2)Some experimental studies have shown that β-catenincan regulate the expression of EAAT2, GLT-1 and GS[57, 106–108]. β-catenin knockout leads to theinhibition of glutamate neurotransmission [109].Figure 2. The WNT pathway and glutamate in AD. Under physiological conditions, glutamate released from the presynaptic neuronstimulates ionotropic glutamate receptors present on the postsynaptic neuron. The resulting influx of Na and Ca2 into the cell leads todepolarization and generation of an action potential. However, chronic elevation of glutamate through impairment of EAAT2 and GS causesneuronal damage and leads to AD. In AD, the downregulation of β-catenin signaling inhibits the activity of EAAT2. Chronic accumulation ofglutamate (through an impaired EAAT2 function, as glutamate reuptake function) induces excitotoxicity and then, neuronal death.www.aging-us.com3099AGING
Moreover, β-catenin expression acts in concordancewith its downstream targets, as TCF/LEF, to controlEAAT2 and GS expression [57]. In parallel, somestudies have shown the potential role of NF- Β in thecontrol of EAAT2 expression [110]. Evidencehighlights the decrease of WNT/β-catenin pathway inrats presenting increase in neuroinflammation [91].WNT/β-catenin pathway is mainly associated withoxidative stress and neuroinflammation [47, 111–113].These signals, act in vicious circle with downregulatedβ-catenin expression, which in turn, downregulate theexpression of EAAT2/GS and then, glutamateexcitotoxicity [57, 114].AD: LOW ATP PRODUCTION ANDDECREASED WNT/β-CATENIN PATHWAY(FIGURE 3)Cerebral hypo-metabolism is associated with theseverity of symptoms observed in AD [115]. Thedecrease in glucose transport in AD brains is caused bythe decrease in energy demand related to thedysfunction of AD synapses [17].Glut-1 (glucose transporter 1) expression, which have amain role in glucose transport in brain [116], isdecreased in AD [117]. After glucose entered in cell,glucose is transformed into glucose-6-phospate by theenzyme Hexokinase (HK). Amyloidogenic AD inmouse models and in post-mortem brains showdecreased levels of HK [118]. Then, glycolysis endingstage is formed by phosphoenolpyruvate (PEP)conversion into pyruvate. Tis step is catalyzed by thepyruvate kinase (PK) with an ADP. PK is composed byfour isoforms (PKR, PKL, PKM1 and PKM2). Lowaffinity with PEP characterizes PKM2 [119].High concentration of glucose leads to acetylation ofPKM2 to reduce its activity and then, targets towa
activation of the WNT/β-catenin pathway may be an interesting therapeutic target for AD [18, 19]. www.aging-us.com AGING 2020, Vol. 12, No. 3 Review Riluzole: a therapeutic strategy in Alzheimer’s disease by targeting the WNT/β-catenin pathway Alexandre Vallée1,
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Therapeutic Recreation Program Undergraduate Handbook Page 2 of 18 2010-2011 Therapeutic Recreation at Temple University Therapeutic Recreation (TR) is an established discipline in health care and human services. The undergraduate curriculum in TR, which allows students to study to become recreation therapists,
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