Page - 56 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 Fractalkine isaproteinexpressedconstitutivelybyneurons inamembraneboundformthatcan becleavedbydisintegrinandmetalloproteinase(ADAM)10and17.Thisproteolysisreleasesasoluble formoftheprotein,butbothisoformsarethoughtto ligate thecognatereceptor,CX3CR1, locatedonthe surfaceofmicroglia in theCNS[42]. Thisneuron-glia interactionservesasan importantendogenous mechanismtosuppressmicroglialactivationandregulatetheoutputofinflammatorymediatorsandother damagingmolecules[42]. IthasbeenshownthatincreasingfractalkinelevelsusinganAAV9genetherapy approachcanbeneuroprotective[35,36],whiletheabsenceofthisFKN-CX3CR1signalingcascadeconfers susceptibility toneurodegeneration in rodentmodels of PD.Cardonaetal. (2006) demonstrated that CX3CR1deficiencyleadtoincreaseneurotoxicitytobothperipheralLPSandMPTPinjections. Inthese experiments,bothheterozygousandhomozygousmiceexhibitedincreasedneurodegenerationandIL-1β expressioncomparedtotheintactwild-typecontrols [43]. Thereisevidenceindicatingthatfractalkinecan regulatemicroglial functionandsubsequentlyreduceinflammationintheCNS.Multiple invitrostudies haveestablishedthatenhancingfractalkinesignalingthroughapplicationof the ligandorstimulation of the receptor canprotect against cell death in culture; FKN-liganddecreasesmicroglial apoptosis andprotectsagainstneurotoxicitybybothLPSandTNF-α. Ithasbeendemonstratedthatmaintaining or enhancing communication of FKN/CX3CR1 is neuroprotective inmultiple rodentmodels of PD. Pabonetal. (2011) [37]attenuatedtheneurotoxicityof6hydroxydopamine(6OHDA)bydelivering achronic intrastriatal infusionofrecombinant fractalkine ligand. Thispreservationofdopaminergic terminals in thestriatumwasalsoassociatedwithdecreasedmicroglialactivationaroundthe lesion site, indicatedbyareducedexpressionof theMHCIIsurfacemarker. Tofurtherexaminetheaction of fractalkine inamodelofPDwheresynuclein is introduced in theSNviaAAV,Nashetal. (2015) corroboratedtheneuroprotectiveeffectsofFKNbyusingaviralvector tooverexpress thedifferent isoformsofFKN;membrane-bound(mFKN)orthesolubleportion(sFKN).Inthisstudy,sFKNreduced DAcell death in young ratswith overexpressionα-syn in the SNviaAAV9. Thesefindingsmay bedue toalteredFKN-CX3CR1signaling [44] anda reduction inpro-inflammatory cytokines and modulationofmicroglial function intoamoreprotective role (Figure1). These results suggest that supraphysiological levelsof the fractalkineareprotectiveagainst theneurodegenerationoccurring in twoseparateexperimentalmodelsofPD.Morgantietal. (2012) [36]also illustratedthe importance ofneuron-glial communicationbyadministeringMPTPtoanimalsdeficient in the fractalkine ligand. TheseFKNknockoutswereextremelysusceptible toMPTPtoxicity,anddisplaybothadramatic loss ofTHintheSNandtherobustgliosisassociatedwith the lesionsite.Notonlydoes thiswork indicate thatFKN-CX3CR1communication isnecessary formoderatingcelldeathandsubsequentdetrimental inflammatory events, but it also suggests that further enhancing or supplementing this signaling pathwayabovebaselineactivity is sufficient toachieveneuroprotectionagainst thesepotent toxins (Figure1). However, theactionof fractalkine isquite complex;CX3CR1knockoutmicehavebeen shownto increasephagocytosisofamyloid,butdecreasephagocytosisof synuclein [44]. It isunclear if thisaction ismediatedbymembraneboundfractalkineor thecleaved, soluble form. Several studies have triedtoclarify therolesof thedifferentialprocessingof fractalkineandtheredoesnotappear to beaclearconclusionat thispoint.Whenanobligatesolubleversionof fractalkine isused,asdescribed herewithagene therapyapproach, ithasbeenshowntobebeneficial inmodelsofPDandADtau pathology[35,36,45].However, inothermodelswhereanobligatesoluble fractalkinemouse isused, oppositeresultshavebeenobserved,andthispaperconcludesthat themembraneanchoredfractalkine isassociatedwithphagocytosisofAβ [46]. Much of the current data regarding the therapeutic potential of FKN in the treatment of inflammatoryandneurodegenerativeconditionsstemsfromstudiesinvolvingyounganimals.However, it is essential to note that aged microglia have been shown to be resistant to their regulatory signals [20,47]. Furthermore,communicationvia theFKN/CX3CR1axisbecomesdysregulatedwith ageandcanalsocontribute tomicroglialpriminganddysfunction. Thereareageassociatedchanges affectingboth the ligandand receptor. It has beenhas shown that FKN is reducedby in the aged hippocampus [48], although the extent of FKN downregulation in the SN has not yet been fully 56