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Jiangetal.MolecularNeurodegeneration2014,9:6 http://www.molecularneurodegeneration.com/content/9/1/6 REVIEW Open Access ’ Trafficking regulation of proteins in Alzheimer s disease Shangtong Jiang1,2†, Yanfang Li2†, Xian Zhang2, Guojun Bu2,3, Huaxi Xu1,2,4 and Yun-wu Zhang2* Abstract The β-amyloid (Aβ) peptide has been postulated to be a key determinantinthe pathogenesis ofAlzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β-and γ-secretases.APPand relevant secretases are transmembrane proteins and traffic through thesecretory pathway in ahighlyregulatedfashion.Perturbation oftheirintracellular trafficking mayaffectdynamicinteractionsamongthese proteins, thus altering Aβgeneration and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD. Keywords: α-secretase, Amyloid beta (A4) precursor protein, β-secretase, Beta-site APP-cleaving enzyme 1, γ-secretase, ADisintegrin and Metalloprotease 10,Alzheimer’sdisease,Trafficking Introduction APP β-carboxyl-terminal fragment (β-CTF) is then Alzheimer’s disease (AD) is a progressive neurodegenera- cleavedbytheγ-secretasecomplexwithinthelipidbilayer, tive disorder characterized clinically by cognitive and resulting in the production of Aβ peptide and the APP memory dysfunction, accompanied by classical hallmark intracellular domain (AICD). Alternatively, processing pathologies such as intraneuronal neurofibrillary tangles within the non-amyloidogenic pathway involves APP (NFTs) and extracellular amyloid plaques [1-3]. NFTs cleavage by α-secretase within the Aβ domain. The α- are enriched withhyperphosphorylated microtubule-asso- cleavage releases the extracellular domain of APP called ciated protein tau (MAPT) [2], which can be phospho- sAPPα. The remaining membrane-bound fragment is rylated by multiple protein kinases. Amyloid plaques called APP α-CTF and can be further processed by γ- comprise a heterogeneous population of proteolytically- secretase to generate AICD and a p3 peptide that is rap- generatedsmallβ-amyloidpeptides(Aβ)[1,4,5].Mounting idly degraded [1,10]. Whether APP is processed through evidence indicates that overproduction/aggregation of Aβ the amyloidogenic pathway by β-secretase or through the in the brain is a primary cause of AD. According to the non-amyloidogenic pathway by α-secretase greatly de- “amyloid cascade hypothesis”, neurotoxic Aβ may trigger pends on colocalization between APP and these secre- acascadeofcomplexneurodegenerativeeventsleadingto tases, which in turn is dependent on their subcellular co- synaptic dysfunction, NFT formation and eventually distribution. Hence, comprehensive elucidation of the neuronlossinaffectedbrainareas[6-9]. mechanisms responsible for regulating the intracellular Aβisgeneratedfromamyloidbeta(A4)precursorpro- traffickingofAPPandrelatedsecretasesareimportantas- tein (APP). APP can be processed by amyloidogenic and pectsinourunderstandingofADandADpathogenesis. non-amyloidogenic pathways. Amyloidogenic processing involves initial APP cleavage by β-secretase within the RegulatedtraffickingofAPP ectodomain, leading to the release of a soluble APPfrag- ment called sAPPβ. The remaining membrane-anchored APPanditstraffickingroutewithinthecell APP is a ubiquitously-expressed type I transmembrane protein belonging to a family comprising three members: *Correspondence:[email protected] APP, APP-like protein 1 and APP-like protein 2, all of †Equalcontributors which share a highly conserved extracellular region con- 2InstituteofNeuroscience,CollegeofMedicine,XiamenUniversity,Xiamen, Fujian361102,China taining Kunitz protease inhibitor (KPI), E1 and E2 do- Fulllistofauthorinformationisavailableattheendofthearticle mains[11,12].However,onlyAPPcontainstheAβregion. ©2014Jiangetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.TheCreativeCommonsPublicDomainDedication waiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwise stated. Jiangetal.MolecularNeurodegeneration2014,9:6 Page2of13 http://www.molecularneurodegeneration.com/content/9/1/6 There are three major APP protein isoforms: APP770, APPstructureandpost-translationalmodificationaffectits APP751 and APP695. The longer isoforms APP770 and trafficking APP751 contain the KPI domain, whereas APP695 is The intracellular domain of APP is key in regulating APP devoid of this domain and is the predominant iso- traffickingthroughinteractionswithvariouscytosolictraf- form expressed in the brain [13,14]. APP participates in fickingfactors.AhighlyconservedYENPTYmotif(amino multiple cellular events including cell adhesion, neurite acids 682–687 in APP695) within APP intracellular do- outgrowth,neuronalmigration,proteintransport,cellsig- main is the major binding site for a number of intracel- naling and synaptogenesis. For a more complete review lular adaptors such as APP-binding, family A (APBA, onthefunctionofAPPpleasesee[1]. previously called MINT) members and APP-binding, Full-length APP is synthesized in the endoplasmic family B, member 1 (APBB1, previously called Fe65) [23]. reticulum (ER) and transported through the Golgi/trans- Mutation within this motif can attenuate the interna- Golgi network (TGN) apparatus where APP undergoes lization of APP, thereby decreasing Aβ generation [24]. posttranslational modifications such as glycosylation and Recently, the extracellular domain of APP has also been phosphorylation during maturation. TGN is also the shown to affect its trafficking: the KPI domain located in majorsiteofresidentAPPinneurons[15-17].Full-length the APP751 extracellular region promotes sorting of APP can be transported to the cell surface in TGN- APP751 to the plasma membrane, accompanied by de- derived secretory vesicles. At the plasma membrane APP creased Aβ formation in comparison to the neuronal is either cleaved by α-secretase to produce sAPPα [18] or enriched, KPI domain-absent APP695 isoform. Mutation re-internalizedwithinclathrin-coatedvesiclestotheendo- in the KPI domain of APP751 results in its retention in some. APP in the endosome can either be recycled back theERandelevatedAβproduction[25]. to cell surface or be delivered to the lysosome for degra- APPcanbephosphorylatedatsitesS655andT668(based dation(Figure1)[19,20].Aβproductioninvolvesmultiple onAPP695numbering)andAPPphosphorylationmayalso intracellular organelles [15-17,21,22]. Typically, increased affect its trafficking. A YTSI (amino acids 653–656 in APPdeliverytoordecreasedAPPinternalizationfromthe APP695) motif within the APP intracellular domain is cell surface favors the non-amyloidogenic processing, associated with APP internalization and Golgi polarized whereaselevatedretentionofAPPinacidiccompartments sorting in MDCK epithelial cells; and phosphorylation of such as endosomes promotes amyloidogenic processing S655 within this motif promotes APP retrieval from the andconsequentAβproduction. endosome to TGN [26,27]. Phosphorylation of APP T668 Figure1TypicaltraffickingrouteofAPP,BACE1,α-secretaseandγ-secretase.NewlysynthesizedAPP,BACE1,α-secretaseandγ-secretase trafficthroughthesecretorypathway,fromtheERtoGolgi/TGNandtotheplasmamembrane,duringwhichprocessretrievalmayoccurandAPP maybecleavedtogenerateAβ.AttheplasmamembraneAPPislargelysubjectedtonon-amyloidogenicprocessingbyα-secretasetoreleasesAPPα. Un-cleavedAPPandvarioussecretasesattheplasmamembranemayundergoendocytosisviaearlyendosometolateendosome/lysosomefor degradation.Acidicendosome/lysosomeprovidesoptimalenvironmentforBACE1activityandAPPismainlysubjectedtoamyloidogenicprocessing forAβproductioninthesecompartments.Inaddition,afractionoftheseproteinsinendosomecanbeeitherrecycledbacktoplasmamembraneor retrievedbacktoTGN. Jiangetal.MolecularNeurodegeneration2014,9:6 Page3of13 http://www.molecularneurodegeneration.com/content/9/1/6 facilitates amyloidogenic APP processing and Aβ ge- (intracellularly or extracellularly) and specific linker neration [28]. Although direct evidence linking T668 proteins involved. A new member of LDLR family, phosphorylationandAPPtraffickingisscarce,T668phos- LRP10, is found to shuttle between plasma membrane, phorylationmayinterfereAPP’sinteractionwithotherpro- TGN and endosome [45,46], and interacts with the APP teins and thus potentially affect its processing/trafficking ectodomain to sequester APP in Golgi compartments, [29].Indeed,phosphorylatedAPPisfoundtobepreferen- thereby reducing APP β-processing and consequent Aβ tially enriched at nerve terminals and plasma membrane generation[47]. in neurons, and accumulates in pathological damaged The best characterized LDLR family member in AD is regionsofADbrains[30]. SORL1, a multifunctional neuronal receptor that binds APP can be ubiquitinated for its proteasomal degra- APOE and APP. Genetic studies have identified multiple dation. But ubiquitination of APP may also inhibit inherited variants in the SORL1 gene associated with its endocytosis to endosomal compartment and thereby late-onset AD [48-51]. In addition, SORL1 level is de- lowerAβgeneration.Insupportofthisnotion,theE3ubi- creased dramatically in frontal cortex and lymphoblasts quitinligasecomponentFBL2canpromoteAPPubiquiti- from AD patients [52]. A correlation between decreased nation and suppress its endocytosis [31]. In addition, an SORL1 expression and impaired cognitive function is ubiquitin-like protein, ubiquilin-1 (UBQLN1), can stimu- also observed [53]. Although the exact physiological late K63-linkedpolyubiquitination atAPP K688toinhibit function of SORL1 has yet to be determined, its ho- APP maturation and delay APP proteolytic processing mology with sorting receptors that are involved in the through APP sequestration primarily within the Golgi transportation between plasma membrane, endosomes apparatus [32,33]. Interestingly, variants in the UBQLN1 and Golgi suggests the protein trafficking function gene have been proposed to be associated with AD of SORL1 [54,55]. Indeed, SORL1 has been found to [34], implying that UBQLN1-mediated APP trafficking/ localize mainly in late endosomal and Golgi com- processingmightbealteredinAD. partments and overexpression of SORL1 redistributes APP to the Golgi and reduces Aβ generation, whereas TheLDLRfamilyinAPPtrafficking downregulation of SORL1 promotes APP sorting into The low density lipoprotein receptor (LDLR) family con- Aβ-generating compartments to aggravate Aβ produc- sists of a number of cell surface receptors of diverse tion [51,56-58]. These data indicate that SORL1 plays functions, including the LDLR, LDLR-related protein 1 important roles in AD pathology by regulating the (LRP1), LDLR-related protein 1B (LRP1B), LDLR-related localizationandprocessingofAPP. protein 2 (LRP2), LDLR-related protein 4 (LRP4), LDLR- related protein 5 (LRP5), LDLR-related protein 6 (LRP6), TheRABGTPasefamilyinAPPtrafficking LDLR-related protein 8 (LRP8, also known as APOER2), RABs comprise a subfamily of small molecular weight LDLR-related protein 10 (LRP10), LDLR class A domain GTPases within the RAS superfamily which regulates containing3(LDLRAD3),sortilin-relatedreceptor,(LDLR cellular trafficking. In humans, over 60 RAB family class)Arepeatscontaining(SORL1,alsoknownasSorLA members have been described so far [59]. RABs func- orLR11),etc. [35,36].ManyLDLRfamilymembersactas tion as molecular switches, alternating between active receptorsforapolipoproteinE(APOE),whoseallelicpoly- GTP-bound and inactive GDP-bound forms [60]. RABs morphisms are strongly associated with late-onset AD regulate protein transport mainly by tethering/docking [37], further implicating the involvement of LDLR family vesicles to target compartments [60]. Multiple RABs members in AD. Recently several LDLR family members have been implicated in regulating APP trafficking. For have been shown tomodulate APP trafficking/processing. example, RAB1B plays a key role inAPPtransport from For example, LRP1 can bind APP directly or indirectly the ER to Golgi. A dominant-negative RAB1B mutant through the adaptor protein APBB1/Fe65 and promote blocks APP ER/Golgi transport and significantly inhi- rapidAPPendocytosistoearlyendosomestopromoteAβ bits Aβ secretion [61]. In addition, RAB6 functions production [38,39]. In contrast LRP1B can compete with as a negative regulator of APP anterograde transport LRP1 for APP interactions and due to its comparatively throughTGN or as a positive modulator of APP retro- slowrateofendocytosiscomparedtoLRP1,LRP1Bretains grade transport from post-Golgi vesicles back to TGN APPatcellsurfaceandsuppressesAβgeneration[40,41]. or Golgi cisternae; and a dominant-negative RAB6 Another LDLR family member, LRP8/APOER2 can mutant facilitates the anterograde transport of APP in interact with APP intracellularly via APBA/MINT and the secretory pathway to promote α-cleavage [62]. DAB1 [42,43] or extracellularly via SPON1 (also known Furthermore, RAB8 facilitates APP transport between as f-spondin) [44]. APP trafficking and resultant non- the Golgi apparatus and plasma membrane and mu- amyloidogenic oramyloidogenicprocessingisdependent tations in RAB8 results in the reduction of sAPPα on the nature of LRP8/APOER2 and APP interactions secretion[63,64]. Jiangetal.MolecularNeurodegeneration2014,9:6 Page4of13 http://www.molecularneurodegeneration.com/content/9/1/6 TheSNXfamilyinAPPtrafficking deficiency results in increased APP trafficking to the Sorting nexins(SNXs)are a diversegroup ofcellulartraf- plasma membrane, whereas familiar AD-linked PS1 mu- ficking proteins that characteristically comprise a cano- tantsdramaticallyreducecellsurfacedeliveryofAPP[75]. nical phospholipid-binding domain. The ability of SNXs PS1 has been proposed to interact with APP and this to bind specific phospholipids, as well as their propensity might be a potential mechanism for its function in regu- to form protein-protein complexes, suggests a role for lating APP trafficking. Alternatively, PS1 might regulate these proteins in membrane trafficking and protein sor- APP trafficking through interactions with trafficking fac- ting [65,66]. Recently, several SNX members have been tors such as RAB family members and phospholipase D1 found to participate in APP metabolism/Aβ generation: (PLD1) [76-80]. PLD1 is a phospholipid-modifying en- SNX33 interacts with the endocytic GTPase dynamin zyme regulating membrane trafficking events and PLD1 and overexpression of SNX33 reduces the rate of APP overexpression itself also promotes APP transport from endocytosis in a dynamin-dependent manner, leading to TGNtotheplasmamembrane[79,80]. enhaced α-cleavage at the cell surface [67]. In addition, SNX17 can bind to APP in the early endosome and Regulatedtraffickingoftheβ-secretaseBACE1 SNX17 downregulation causes a decline in steady-state BACE1anditstraffickingpathwayswithinthecell levels of APP with a concomitant increase in Aβ pro- It is well accepted that beta-site APP-cleaving enzyme 1 duction[68]. (BACE1) is the dominant β-secetase enzyme for APP [81-84]. BACE1 is a 501 amino acid long type-I trans- TheAPBA/MINTfamilyinAPPtrafficking membraneaspartylproteasecomprisingaprodomainwith The APBA/MINT family is an adaptor protein family significant homology to other aspartyl protease pre- comprisingAPBA1/MINT1,APBA2/MINT2andAPBA3/ cursors. Overexpression or downregulation of BACE1 in- MINT3. All three proteins are enriched in neurons and duces or inhibits APP processing and Aβ generation both contain a phosphotyrosine binding (PTB) domain in the in vitro and in vivo [81-85]. Several studies find that central region and two tandem carboxyl-terminal PDZ BACE1 level and activity are elevated significantly in AD (PSD-95, Drosophila disks-large, ZO-1) domains. Moun- brain [86,87]. In addition, in an APP overexpression AD ting evidence indicates that the APBA/MINT family is mouse model, deletion of BACE1 can abolish Aβ pa- involved in multiple cellular activities relevant to neuro- thology and rescue cholinergic dysfunction and memory nal protein transport and consequent synaptic function deficits [88-90]. These findings suggest that BACE1 may [69-71]. APBA/MINT proteins can interact with the APP be a good therapeutic target for AD treatment. On the YENPTY motif through their PTB domains to fine-tune other hand, more recent studies have found that in APP trafficking and processing [70,71]. For instance, additiontoAPP,thereareotherBACE1substratesinclud- APBA1/MINT1 has been found to modulate both ing neuregulin 1 [91,92], p-selectin glycoprotein ligand-1 secretory and endocytic trafficking of APP and its meta- [93], ST6GAL1 [94], β-subunits of voltage-gated sodium bolism[71].Inaddition,APBA2/MINT2canbephosphor- channels [95], etc. This raises a possibility that inhibition ylated by SRC toaccelerate APP endocytosis and enhance ofBACE1mightaffectproperprocessingoftheseproteins APP sorting to autophagosomes, leading to enhanced andcauseunwantedsideeffects.BACE1nullmicedode- intracellular Aβ accumulation. Conversely, an APBA2/ velop several phenotypic abnormalities such as reduced MINT2 phospho-resistant mutant promotes APP traffic- body size, hyperactive behavior, decreased grip strength king in the recycling pathway to the cell surface, thus en- and elevated pain sensitivity [91,92,96]. Recently Eli Lilly’s hancing Aβ secretion [72]. Furthermore, APBA1/MINT1 BACE1inhibitorLY2886721wasalsofoundtocauseliver or APBA2/MINT2 may function as a linker to mediate toxicity duringits Phase 2 clinical trial. However, it is un- co-endocytosis of LRP8/APOER2 and APP, thereby eleva- clear whether abnormal phenotypes found in BACE1 null ting Aβ production [42,73]. Finally, APBA3/MINT3 also micearegeneratedduringdevelopmentalstagesorduring playsanobligatoryrolein mediating APPtraffickingfrom aging;and LY2886721-caused liver toxicityisnotbelieved the TGN to the plasma membrane and its deficiency to be attributed to BACE1 inhibition. Furthermore, reroutes APP trafficking to the endosomal/lysosomal BACE1heterozygousknockoutmicehavenoreportedab- pathway[74]. normal phenotypes so far and heterozygous knockout of BACE1stillcanreduceAβdepositioninADmice[97,98]. OtherproteinsinvolvedinAPPtrafficking Hence,moderateinhibitionofBACE1activitymaystillbe Inadditiontogeneraltraffickingmodulators,severalother agoodstrategyforADtreatment. proteins have also been proposed to regulate APP traf- Like other aspartic proteases, immature BACE1 con- ficking. For example, we and others have shown that pre- taining the short prodomain is initially synthesized in senilin1(PS1),the catalyticcomponentoftheγ-secretase the ER and subsequently transported to the Golgi appa- complex, can regulate APP intracellular trafficking: PS1 ratus where the prodomain is removed by FURIN or Jiangetal.MolecularNeurodegeneration2014,9:6 Page5of13 http://www.molecularneurodegeneration.com/content/9/1/6 otherFURIN-likeproteases[99-102].Removalofthispro- of GGA3 also increases BACE1 levels [120,121]. More- domain leads to a ~2-fold increase of BACE1 activity over, BACE1 can be ubiquitinated at K501 and a GGA3 [103]. BACE1 can also be N-glycosylated and mature mutant with reduced ubiquitin-binding ability fails to BACE1 is exported either to the plasma membrane or to regulate BACE1 levels, implying that GGA3 may also theendosomalcompartment.Plasmamembranelocalized regulate BACE1 via interactions with ubiquitin sorting BACE1 can be internalized into the endosome, whereby machinery[122]. BACE1 can be recycled to the plasma membrane or transferred to late endosomal/lysosomal compartments TheretromercomplexandtheSNXfamilyinBACE1 (Figure1).AsoptimalBACE1activityisachievedinacidi- trafficking fied environments, BACE1 is mainly found in acidic sub- ThemammalianretromercomplexiscomposedofVPS35, cellular compartments such as endosome [82,104-107]. VPS29, VPS26, SNX1 and SNX2 [123]. Retromer is re- Therefore,anymodulatorthatcanaffectBACE1shuttling quired for protein endosomal sorting and is closely linked betweenTGN,theplasmamembraneandendosomemay totheendosome-to-Golgiretrievalpathway.Retromerwas playaroleinAPPprocessingandAβgeneration. first identified to sort VPS10 from endosome back to the TGN in yeast [123]. Recent studies have identified some TheGGAfamilyinBACE1trafficking retromer interacting proteins including SORL1 [124] and Golgi-localizedγ-adaptinear-containingADPribosylation BACE1 [125]. Suppression of VPS35expressiondecreases factorbindingproteins(GGAs)areafamilyofmonomeric BACE1 trans-Golgi localization and retains BACE1 in the clathrin adaptor proteins that participate in transport of endosome, the optimal environment for BACE1 activity. cargoproteinsfromTGNtoendosome[108].Mammalian Consistently, heterozygous deletion of VPS35 in AD mice GGAs(GGA1,GGA2,andGGA3)allcompriseanamino- results in a significant increase in Aβ level in the mouse terminalVHS(VPS-27,Hrs,andSTAM),anintermediary hippocampus, accompanied with AD-like phenotypes in- GAT (GGA and Tom1) and a carboxyl-terminal GAE cludingcognitivememorydeficits,defectivelong-termpo- (γ-adaptinear)domain[108]. VHSand GATdomainsare tentiation (LTP) and impaired postsynaptic glutamatergic highly conserved among GGA1, GGA2 and GGA3 [109]. neurotransmission in early adult age [125]. One recent Recruitment of GGAs from the cytosol to TGN is me- study also found that downregulation of VPS35 in neu- diated by the GAT domain [109-111]. Subsequent GGA rons results in increased colocalization of APP with the VHS domain binding to the acidic cluster-dileucine BACE1inearlyendosomesandconsequentlyelevated Aβ (ACDL) sorting motif within the cytoplasmic tails of levels[126].Similarly,downregulationofanotherretromer selective cargo proteins then sorts the selected cargo componentVPS26inducestheaccumulationofBACE1in into clathrin-coated vesicles that are delivered to the endosome [114]. Coincidently, the levels of VPS35 and endosome[112]. VPS26arefoundtobedownregulatedinAD[127]. The BACE1 DISLL (amino acids 496–500) sequence is The existence of two SNX family members, SNX1 and anACDLmotiflocatedintheBACE1cytoplasmicdomain SNX2withintheretromercomplexhasprovidedalinkfor andcanberecognizedbytheGGAVHSdomain[113,114]. SNXs in regulating BACE1 trafficking. SNX6, a SNX2-like PreviousstudiesindicatethatGGA1modulatesBACE1re- retromerregulator,caninteractwithBACE1andnegatively trieval from the endosome to TGN in a phosphorylation- regulate its retrograde transport from early endosomes to dependent manner. Serine phosphorylation within the TGN, retaining BACE1 in endosome [128]. We recently BACE1 DISLL motif enhances BACE1-GGA interaction identified SNX12 as another BACE1-interacting protein [115]. Phosphorylated BACE1 is efficiently transported anddemonstrateditsroleinmodulatingBACE1trafficking from endosomes to TGN, whereas non-phosphorylated betweenthecellsurfaceandearlyendosome[129]. BACE1entersadirectrecyclingroutetotheplasmamem- brane [114,116,117]. Overexpression of GGA1 decreases OtherproteinsinvolvedinBACE1trafficking Aβ secretion, while suppression of GGA1 conversely ele- Thereisevidence suggestingthat endocytosis of APP and vatesAβsecretion[116].Inaddition,arecent studyshows BACE1 are spatially separate: in contrast to clathrin- thatGGA1butnotGGA2orGGA3canmodulateSORL1 dependent APP endocytosis, BACE1 internalization to endocytictrafficandconsequentAPPtraffictotheendocy- early endosome is found to be regulated by the small ticrecyclingcompartment[118].Furthermore,mutationof GTPase ADP ribosylation factor 6 (ARF6). Modulation of BACE1 S498 to a non-phosphorylatable residue enhances ARF6 levels or its activity affects endosomal sorting BACE1 targeting to SORL1-positive compartments [118]. of BACE1 and altered APP processing/Aβ production. In contrast, GGA3 is proposed to mediate targeting of Furthermore, APP is cleaved by BACE1 in RAB5-positive BACE1 to lysosomes for degradation [119-121]. In AD earlyendosomeandsortingofBACE1fromARF6-positive brains, GGA3 level is significantly decreased and inversely towards RAB5-positive early endosome depends on the correlated with elevated levels of BACE1. Downregulation BACE1DISLLmotif[130]. Jiangetal.MolecularNeurodegeneration2014,9:6 Page6of13 http://www.molecularneurodegeneration.com/content/9/1/6 Inadditiontoitscarboxyl-terminus,thetransmembrane Assemblyoftheγ-secretasecomplexanditstrafficking domain of BACE1 may also affect its trafficking. We routewithinthecell recently found that the heavy components of the CUTA Although aspects of γ-secretase complex formation and protein can interact with the BACE1 transmembrane distribution have yet to be fully elucidated, a predicted region. Downregulation of CUTA decelerates BACE1 modelfortheassembly,maturation,and traffickingofthe transport from Golgi/TGN to the plasma membrane and γ-secretasecomplexhasbeenproposed.Inthismodel,the reduces steady-state levels of cell surface BACE1, thus four components of the γ-secretase complex are synthe- resulting in increased Aβ generation [131]. Furthermore, sizedintheER,wheretheyawaitincorporationintostable BACE1caninteractwiththereticulonfamilyproteinsand complex. Complex formation initially begins with the this is mediatedby BACE1transmembrane domain[132]. associationofAPH-1andnicastrintoformanearlyinter- The reticulon family has four members, RTN1, RTN2, mediate subcomplex. Full-length PS is then incorporated RTN3andRTN4(alsoknownasNogo),andisinvolvedin intoandstabilizedwithinthecomplex.Subsequentassem- various physiological processes such as membrane traf- bly of PEN2 drives the conversion of the full-length PS ficking, axonal growth and apoptosis [133]. Overex- intoactiveNTF/CTF heterodimersinER and Golgicom- pression of any reticulon protein has been shown to partments [140,147]. During its transit through Golgi/ substantially reduce Aβ production. In neurons, BACE1 TGN, nicastrin undergoes complete glycosylation, thus mainly colocalizes with RTN3, whose overexpression transforming the γ-secretase complex into its mature can block BACE1 in the ER and thus inhibit BACE1 ac- form. The γ-secretase complex in large part shuttles tivity for Aβ generation [134,135]. Interestingly, recep- between the ER and Golgi, whereas stabilized mature tors of reticulon have also been found to mediate Aβ γ-secretase complex is transported to the plasma mem- production but this is through their interaction with brane. γ-secretase at the membrane can then undergo APP. Increased interaction between reticulon receptor endocytosis to endosomes, and subsequent trafficking to and APP can reduce surface expression of APP and late endosomes/multivesicular bodies or the lysosome favorsAPPβ-cleavage[136,137]. (Figure1)[148-151]. Regulatedtraffickingoftheγ-secretasecomplex Factorsregulatingγ-secretasetraffickingandactivity Theγ-secretasecomplex In addition to its function as the catalytic core of the BACE1-digested APP CTFs are subsequently cleaved γ-secretase complex, PS1 has been shown to modulate by the γ-secretase complex to release Aβ. In addition, trafficking of several transmembrane proteins including γ-secretase cleaves a series of functionally important APP [75]. Since PS1 interacts with a series of trafficking substrates such as NOTCH [138] and tyrosinase [139]. modulator proteins such as RAB family members and γ-secretase activity is produced from a high molecular PLD1, PS1 might exert its trafficking regulation through weight complex consisting of at least four transmem- these interactions [152]. Conversely, these trafficking branecomponents:presenilin(PS,withtwomammalian modulators may also reciprocally regulate PS1 traffic- homologs as PS1 and PS2), nicastrin, anterior pharynx- king. For example, we find that PLD1 interacts with PS1 defective-1 (APH-1), and presenilin enhancer-2 (PEN2) and overexpression of PLD1 promotes cell surface accu- [140,141]. PS1/2 have an undetermined number of mulation of PS1 in an APP-independent manner [153]. transmembrane domains [142] and undergo endo- A trafficking regulation role has been proposed for APP proteolyticcleavagetogeneratePSamino-terminalfrag- [154]andwe alsofindthatAPPcan reciprocallyregulate ments (NTFs) and CTFs. PS NTF and CTF form a the intracellular trafficking of PS1 and other γ-secretase functional heterodimer, each contributing a highly con- components.APPdeficiencyresultsinelevatedtranspor- served aspartate residue indispensable for γ-secretase tation of PS1/γ-secretase from TGN to the cell surface, activity [143]. Nicastrin is a type I transmembrane thereby enhancing NOTCH cleavage [153]. Additionally, glycoprotein considered to be the scaffolding protein APP can function as a kinesin-I membrane receptor and within the γ-secretase complex. Nicastrin may also act mediatesaxonal transportofPS1andBACE1[155]. as the γ-secretase receptor [144]. The seven-transmem- The recently identified postsynaptic protein ARC also brane APH-1 interacts with nicastrin to form a stable interacts with PS1 and participates in sorting PS1 to intermediate in an early assembly stage of the γ- early and recycling endosomes to enhance amyloido- secretase complex [140,141], whereas the two-pass genic APP processing. Aβ production can be blocked by transmembrane component PEN2 regulates PS endo- interrupting ARC association with PS1/γ-secretase and proteolysis [145,146]. Each of these four components is genetic deletion of ARC decreases Aβ load in a trans- necessary for γ-secretase activity and deficiency in any genic ADmousemodel [156]. of these factors dramatically impairs the enzymatic The G protein-coupled receptor (GPCR) β2-adrenergic activity. receptor is associated with PS1 where agonist-induced Jiangetal.MolecularNeurodegeneration2014,9:6 Page7of13 http://www.molecularneurodegeneration.com/content/9/1/6 β2-adrenergicreceptorendocytosismediatestraffickingof ATP-binding cassette transporter-2 (ABCA2) is a PS1/γ-secretase to late endosomes and lysosomes to component responsible for retrograde trafficking of lipo- enhance Aβ production [157]. Another GPCR, GPR3 is protein-derived cholesterol from late endosome/lysosome also found to be a modulator of Aβ production: over- totheER,andhasbeengeneticallylinkedtoAD[166,167]. expression of GPR3 increases the formation and cell sur- It has been recently shown that ABCA2 depletion can face localization of the mature γ-secretase components, reduceγ-secretasecomplexformationduetoalterationsin accompanied with stimulated Aβ generation but not protein levels, post-translational modification, and sub- NOTCH processing. In contrast, GPR3 deficiency pre- cellular localization of nicastrin, thus affecting the γ- vents Aβ accumulation both in vitro and in vivo. More- processingofAPPandAβgeneration[168]. over, GPR3 is highly expressed in normal human brain regions implicated in AD and its level is elevated in spor- Regulatedtraffickingoftheα-secretaseADAM10 adic AD brain [158]. Interestingly, recently it was sug- α-secretase,ADAM10anditstraffickingroutewithinthecell gested that both β2-adrenergic receptor and GPR3 exert α-secretase-mediated APPcleavage leads to the release of theireffectsonAβgenerationthroughinteractingwithβ- sAPPα,andcompetitivelyantagonizesAPPamyloidogenic arrestin2,amemberofthearrestinfamily[159].Arrestins processingandAβgeneration.Theα-secretaseprocessing are GPCR-interacting scaffold proteins and can inhibit G pathway is Protein Kinase C-dependent and its activity protein coupling to GPCRs, leading to GPCR desen- can be modulated by various molecules such as the puri- sitization and even mediating a G protein-independent nergicP2Y2receptor,pituitaryadenylatecyclaseactivating signaling pathway [160]. β-arrestin 2 is found to interact polypeptide, muscarinic receptors and NMDA receptors with APH-1, redistribute the γ-secretase complex toward [169-172]. In addition to APP, several other proteins in- detergent-resistent membranes and increase its catalytic cludingprion,NOTCHreceptors,ephrins,tumornecrosis activity [159]. The degreeofAβ productionstimulation is factor α and cadherins have also been identified as alsocorrelatedwithGPCR-β-arrestin2bindingandrecep- α-secretasesubstrates[119,173-175]. tor trafficking to endocytic vesicles [161]. Moreover, a So far, several ADAM (A Disintegrin and Metallopro- subsetofGPCRsincludingGPR3andPTGER2,arefound tease) family members including ADAM9, ADAM10 tobeassociatedwithAPPwheninternalizedviaβ-arrestin and ADAM17 have been implicated as potential APP 2, thereby increasing APP amyloidogenic processing as α-secretases.Thesetype-ItransmembraneADAMcompo- well [161]. Coincidently, another arrestin family member, nents are prominently expressed in adult central nervous β-arrestin 1, can interact with APH-1 and facilitate the system. However, the expression of ADMA10 is relatively formation of nicastrin/APH-1 subcomplex and mature high compare to those of ADAM9 and ADAM17 in neu- γ-secretase complex. β-arrestin 1 expression is upregu- rons [176-178] and conditional knockout of ADAM10 in latedinthebrainsofsporadicADpatientsandtransgenic mouse neurons nearly abolishes neuronal sAPPα gene- ADmice,whereasdeletionofβ-arrestin1inADmicere- ration [179]. Together, this suggests that ADAM10 is the sults in reduced Aβ generation, diminished Aβ pathology major functional α-secretase in neurons [180,181]. In AD andimprovedcognition[162]. patients,theproteinlevelofADAM10,α-secretaseactivity The retention in ER sorting receptor 1 (RER1), a mem- and consequent sAPPα levels are found to be decreased brane factor mediating protein retrievalfrom Golgitothe significantly in platelets and temporal cortex regions ER, has been found to regulate γ-secretase trafficking. In [182,183]. In contrast, ADAM9 and ADAM17 thus onestudy,RER1wasfoundtobindtothetransmembrane far have only been shown to participate in regulated region of nicastrin and retrieve unincorporated nicastrin α-secretasecleavage[181,184]. from the cis-Golgi back to the ER. Since RER1 competes Newly-synthesizedADAM10intheERhasaproprotein with APH-1 for nicastrin binding, depletion of RER1 re- convertase recognition sequence between the prodomain sulted in elevated γ-secretase complex assembly/activity and the catalytic regions. During its secretory trafficking and increased Aβ secretion [163]. In another study, RER1 to TGN and cell surface (Figure 1), ADAM10 can be was found to bind to the first transmembrane domain of cleaved by PC7 or FURIN to yield a mature, active form PEN2 and retrieve unassembled PEN2 to the ER [164]. [185-187]. In neurons, α-secretase functions predo- BothstudiessuggestthatRER1maybecriticalinmonito- minantly at the cell surface [188], with minor α-secretase ring quality control during γ-secretase complex assembly. activityobservedinTGN[189-191]. Recently, RER1 overexpression was also shown to de- creasebothγ-secretaselocalizationonthecellsurfaceand RegulatedtraffickingofADAM10 Aβsecretion,whereasRER1downregulationhadopposite Anarginine-rich(723RRR)sequencewithintheADAM10 effects [165]. Furthermore, increased RER1 levels could intracellular C-terminal tail is required for its retention decrease mature APP and increase immature APP, resul- in the ER and attenuates trafficking to the cell surface. tinginlesssurfaceaccumulationofAPP[165]. Mutation of the second arginine within the 723RRR Jiangetal.MolecularNeurodegeneration2014,9:6 Page8of13 http://www.molecularneurodegeneration.com/content/9/1/6 sequence is sufficient to allow ADAM10 exit from the Metalloprotease;AICD:APPintracellulardomain;APBA:APP-binding,familyA; ER and enhance ADAM10 distribution to the neuronal APBB1:APP-binding,familyBmember1;APOE:ApolipoproteinE; APP:Amyloidbeta(A4)precursorprotein;ARF6:ADPribosylationfactor6; cellsurface[192]. BACE1:Beta-siteAPP-cleavingenzyme1;CTF:Carboxyl-terminalfragment; ProteininteractionscaninfluenceADAM10localization. DS:Downsyndrome;ER:Endoplasmicreticulum;GAE:γ-adaptinear; Forinstance,interactionswithsynapse-associatedprotein- GAT:GGAandTom1;GGA:Golgi-localizedγ-adaptinear-containingADP ribosylationfactorbindingprotein;GPCR:Gprotein-coupledreceptor; 97 (SAP97), a protein involved in dynamic transport of KPI:Kunitzproteaseinhibitor;LDLR:Lowdensitylipoproteinreceptor; proteins to the excitatory synapses, facilitates ADAM10 LDLRAD3:LDLRclassAdomaincontaining3;LRP1:LDLR-relatedprotein1; targetingtothepostsynapticmembrane.ADAM10-SAP97 LRP1B:LDLR-relatedprotein1B;LRP2:LDLR-relatedprotein2;LRP4:LDLR-related protein4;LRP5:LDLR-relatedprotein5;LRP6:LDLR-relatedprotein6; interaction is triggered by NMDA receptor activation, LRP8:LDLR-relatedprotein8;LRP10:LDLR-relatedprotein10;LTP:Long-term thus promoting the non-amyloidogenic processing of potentiation;NFTs:Neurofibrillarytangles;NTF:Amino-terminalfragment; APP. Conversely, disrupting ADAM10-SAP97 interaction PDZ:PSD-95,Drosophiladisks-large,ZO-1;PLD1:PhospholipaseD1; PS1:Presenilin1;PTB:Phosphotyrosinebinding;RER1:RetentioninERsorting redistributes ADAM10 localization from postsynaptic receptor1;SAP97:Synapse-associatedprotein-97;SNX:Sortingnexin; membranes, thereby suppresses non-amyloidogenic APP SORL1:Sortilin-relatedreceptor,(LDLRclass)Arepeatscontaining;TGN:Trans- processing. As a consequence, this results in Aβ accumu- Golginetwork;VHSVPS-27:HrsandSTAM;UBQLIN1:Ubiquilin-1. lation, MAPT hyperphosphorylation, and impaired be- Competinginterests havioral performance and synaptic dysfunction in mice, Theauthorsdeclarethattheyhavenocompetinginterests. thereby recapitulating early-stage AD phenotypes [193]. In the hippocampus of AD patients, the association of Authors’contributions SJ,YL,XZ,GB,HXandYWZcontributedtothewritingandrevisingofthe ADAM10 with SAP97 is found to be reduced [194], im- manuscript.Allauthorsreadandapprovedthefinalmanuscript. plyingadysfunctioninSAP97-mediatedADAM10sorting in AD. Interestingly, while long-term depression can pro- Acknowledgements WethankDrs.TimothyHuangandXinWangforproofreadingthis mote SAP97-dependent ADAM10 distribution and acti- manuscript.ThisworkwassupportedbygrantsfromtheNationalInstitutes vity in synaptic membranes, LTP can induce ADAM10 ofHealth(R01AG038710,R01AG021173,R01AG044420andR01NS046673), endocytosis and reduce ADAM10 activity through the theAlzheimer’sAssociation,NationalNaturalScienceFoundationofChina (81225008,81000540,81161120496,91332112and91332114),the association of the clathrin-adaptor AP2. Furthermore, FundamentalResearchFundsfortheCentralUniversitiesofChina,andFok ADAM10-AP2associationisfoundtobeenhancedinAD YingTungEducationFoundation. patients [195]. These findings indicate that SAP97 and Authordetails AP2 are critical components in controlling ADAM10 1FujianProvincialKeyLaboratoryofNeurodegenerativeDiseaseandAging localization and activity at synapses to modulate patho- Research,SchoolofPharmaceuticalSciences,XiamenUniversity,Xiamen, physiologyinAD. Fujian361102,China.2InstituteofNeuroscience,CollegeofMedicine,Xiamen University,Xiamen,Fujian361102,China.3DepartmentofNeuroscience, MayoClinic,Jacksonville,Florida32224,USA.4DegenerativeDiseaseResearch Conclusions Program,Sanford-BurnhamMedicalResearchInstitute,LaJolla,California Although APP is a well-characterized substrate of α-, β- 92037,USA. andγ-secretases,thephysiologicalrelevanceofthevarious Received:29November2013Accepted:15December2013 APPprocessingpathwaysisfarfromclear.Amyloidogenic Published:11January2014 Aβ generation from APP clearly contributes to AD- associated neurotoxicity and plays a central role in the References 1. ZhengH,KooEH:Biologyandpathophysiologyoftheamyloidprecursor pathogenesis of AD. A wealth of experimental evidence protein.MolNeurodegener2011,6:27. demonstrates APP cleavage by different secretases at dis- 2. 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