Journal of Cell Science euaoyptwyfrtecnrlo ernlpoentasot n rvd le st h eet nti aha cause pathway this in defects why to unique as a clues uncovered findings provide these and here, transport, discussed As patients. neuronal in of AD for control amyloidogenic factors the enhanced disease. risk and neurodegenerative for defects important transport pathway in represent result and adaptors regulatory interacting APP, its of and SORLA processing in Defects breakdown. amyloidogenic favor eateto imdcn,Aru nvriy K80 ahsC Denmark. C, Aarhus DK-8000 University, Aarhus Biomedicine, of Department noigete P rpeeii- n 2 hc are which -2, and presenilin-1 or the disease the of APP in the mutations components of by either caused forms are encoding They inheritable FAD). rare of AD, (familial A extent from the to stems that APP progression Evidence of AD. breakdown of proteolytic which hallmarks plaques, pathological amyloid and are of oligomers by neurotoxic Some into residues). aggregate polypeptides A acid notably peptide amino precursor peptides, (37–43 these this amyloid length the types, produce fragment various from cell to many cleavage liberated a proteolytic in In is occurs domains. extracellular sequence that and process transmembrane their natural of part as 1 Willnow avoid E. Thomas to path trafficking disease a Alzheimer – SORLA Sorting rti AP,a1010katp- transmembrane type-1 in APP found isoforms three is kDa in APP 110–130 expressed that precursor and is It function amyloid types. characterized cell a the many poorly is of details) (APP), hypothesis for cascade Pivotal 1 2011). amyloid protein underlying Selkoe, Box the 1992; events Higgins, (see to and cellular AD Hardy the 1991; in (Selkoe, of processes description of neurodegenerative the for the concept in widespread 2006). plaques al., as et neuritic (Blennow such individuals and affected anomalies, which degeneration structural impairment, cognitive neuronal by and accompanied loss is characterized memory is AD progressive the dementia. by and age-related of disorder form neurodegenerative common a most is (AD) disease Alzheimer Introduction words: Key of regulator central a as poorly remain emerges of movement AD that retrograde to SORLA and anterograde contribution receptor for their adaptors sorting cytosolic and new of sets a distinct trans in of with the interacts APP between elucidation SORLA APP However, APP. of functional fate. between of processing trafficking moves the processing its and APP intracellular describe determines trafficking whereby secretases the we route various complex control Here, the the encounter that understood. concepts, to current mechanisms to and molecular amyloid According surface neurotoxic the (AD). cell disease to the Alzheimer compartment, (APP) of secretory protein the cause precursor molecular amyloid a is the brain of breakdown proteolytic Excessive Summary 10.1242/jcs.125393 doi: 2751–2760 126, ß Science Cell of Journal ( correspondence for *Authors 2 h udekFudto eerhCne ID aihRsac nttt fTasainlNuocec odcEB atesi,and Partnership, Nordic-EMBL Neuroscience Translational of Institute Research Danish MIND, Center Research Germany Foundation Berlin, Lundbeck 13125 The Medicine, Molecular for Max-Delbrueck-Center 03 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2013. h ayodcsae yohssrpeet ieyaccepted widely a represents hypothesis cascade’ ‘amyloid The RIL EIS elBooyadDisease and Biology Cell SERIES: ARTICLE 770 hc l hr hr mn cdppiesequence peptide acid amino short a share all which , P,Azemrdsae P1-oanrcpos rti rnpr, transport, Protein receptors, VPS10-domain disease, Alzheimer APP, c - sceaecmlxrsosbefrAPP for responsible complex -secretase [email protected] og ewr n al nooe,teeyrsrcigdlvr ftepeusrt noyi oprmnsthat compartments endocytic to precursor the of delivery restricting thereby endosomes, early and network Golgi 1, n lvM Andersen M. Olav and * b 2 xii rnucdtnec to tendency pronounced a exhibit 42, b ; sadtriato AD of determinant a is [email protected] b etds(A peptides 695 2, APP , * b )of ) 751 oad eeaino h oeayodgncvratA variant amyloidogenic more the an of A with generation of associated production towards the are in mutations increase overall FAD Typically, . ecietecmlxtafcigpt fAP n h intrinsic the and APP, of we path section, amyloidogenic trafficking this complex In its the fates. describe determines processing avoid or non-amyloidogenic enter compartments to versus APP of cellular ability distinct the that in certain and reside cell, secretases in the the that of findings factor organelles through the by decisive this initiated moves evidence, was a other idea APP Among is processing. which proteolytic neurons, its controlling by of emerged path, compartments notion the intracellular trafficking processing, APP the on that studies fates during processing on controls Early APP of trafficking Cellular rcsigo P,addsuswydfcsi hs pathways these and in defects trafficking AD. why sporadic proper discuss in and govern result molecular APP, that unique of the a SORLA, processing review of receptor characterization we functional sorting Commentary, the of this cause including APP in major pathways, In a which neurons represent AD. also of by secretases, sporadic by compartments path, cleaved be intracellular complex to order the the the now through in findings for traffics recent disturbances cause However, that a AD. represent show of form also late-onset A mechanisms of common up underlying build aberrant its the whether and determine to difficult more is A in 2011). al., neurodegeneration et of (Karran onset 1) early (Box the cause that mechanisms both A uain aebe ntuetli eihrn defects deciphering in instrumental been have mutations FAD b rdcina h luil as feryostA,btit but AD, early-onset of cause plausible the as production b etds(A peptides omnay2751 Commentary b etdso ihashift a with or peptides b ysceae nthe in secretases by ) b 42, b Journal of Cell Science 2752 abxltriu Vsa ta. 99 a ta. 01.These 2001). al., et Cai 1999; A al., produce steps et (Vassar terminus carboxyl eut ntegnrto famtn A mutant 1992). a al., et of (Kamino generation properties aggregation the in results ain A variant o .Teayodcsaehypothesis APP cascade amyloid The 1. 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Three the the familial 2011). in to depicted close al., cause also or in et that cluster (Karran which of mutations sequence all known, point total are A (FAD) figure. different disease the below 24 given are APP of in a residues adjacent The of as A nucleus. and human the the of act in adaptor sequence Tip60 acid the acetyltransferase amino might histone with the association AICD in and its Fe65 involved The through are regulator with pathways. that transcriptional interact molecules differentiation signaling C83, cellular and and plasma the adaptors as adult synaptic C99 well multiple as the fragments APP, stimulate full-length from membrane-associated of receptors tail to cytoplasmic glutamate The adhesion, membrane. pathway of cell removal receptor the in (EGF) A acts neurogenesis. factor APP and growth Pardossi-Piquard example, sAPP 1997; For whereas Mattson, 2012). processing various in Checler, its and (reviewed APP to products assigned been have functions sAPP as the contrast, A By of by end manner. APP of terminal cleavage non-amyloidogenic ( the by secretase initiated a is pathway amyloidogenic in acts and Because PSENEN). by (APH1), as cleavage known defective-1 also (Pen-2, pharynx -2 presenilin anterior 2010). nicastrin, al., presenilin, et (Kuhn is A APP right), the the within to middle cleaved the from first (Selkoe, (figure, pathway processes one neurodegenerative In 2011). of progression the and determine onset that pathways processing alternative two undergoes lae 8 noppieP n h P nrclua domain candidate metalloprotease intracellular are and ADAM10, APP particularly disintegrin the family, the (ADAM) and of members P3 Several peptide Subsequently, (AICD). into C83 C83. cleaves fragment (sAPP soluble anchored produces which secretase, A β 40 or42 SVMTVIVITLVMLKK ISEVKM 695 AICD wds rtcLondon Arctic Swedish LGI G NL ora fCl cec 2 (13) 126 Science Cell of Journal stemi P sfr xrse nnuosand neurons in expressed isoform APP main the is b b AFHSYVHKLFADGNGIGMGV IA LVFFAEDVGSNKGAIIGLMVGGVV DAEFRHDSGYEVHHQK 42 βα b n h ID(etpr ftefgr) Numerous figure). the of part (left AICD the and st P laigezm-;BC1 tteN- the at BACE1) enzyme-1; cleaving APP -site a Gaee l,19) h rtcmtto (E693G) mutation Arctic The 1991). al., et (Goate γα sceaedsry h A the destroys -secretase a b b etds fmil 0t 2aioais swell as acids, amino 42 to 40 mainly of peptides, sblee ocoeaewt h epidermal the with cooperate to believed is sAPP ouae yatctasiso yinducing by transmission synaptic modulates C99 b olwdby followed , α c sceaei utmrccmlxof complex multimeric a is -secretase b b βγ sceaecevg ieadcue a causes and site cleavage -secretase etd euneb h protease the by sequence peptide APP b c b 40 sceaecevg tits at cleavage -secretase etd hglgtdi blue) in (highlighted peptide otemr amyloidogenic more the to b b sAPP b a etd,ti pathway this peptide, C83 n membrane- a and ) etd ihaltered with peptide Mla ta. 1992). al., et (Mullan c sceaeactivity -secretase γ α 40 c sceaeand -secretase a γ -secretases 42 AICD P3 b a b - - oeo neato ewe R1 n P ih loivleF6 ryet or Fe65 involve The also F-spondin. might and APP adaptors. Fe65 and unknown LRP1B through between mediated interaction sAPP is of to APOER2 mode cleavage to promotes APP but of Binding as delays known also LRP1B (APOER2, and 2 LRP8) endocytic receptor E its apolipoprotein facilitates A receptors surface to endocytosing cell processing the intracellular Fe65-mediated on and types. LRP1 uptake cell with other APP many of and association neurons in expressed receptors ( TGN. P ssbett xesv ottasainlmodifications, post-translational route, extensive En 1A). to (Fig. subject membrane plasma is the APP to (TGN) network mlioei rcsigo nenlzdAPtruhsqeta cleavage sequential through APP by internalized late TGN. of the the processing the to to Amyloidogenic and moves retrogradely APP APP or of endosomes, compartments tail early endosomal-lysosomal cytoplasmic From the AP2. between adaptor interaction clathrin the by which endocytosis, guided clathrin-mediated is through surface cell the from internalize eiuu E)truhteGlicmlxadtrans and complex endoplasmic Golgi the the from move through and (ER) cell the reticulum of pathway 2012; secretory al., et Haass the 2012). 2009; Annaert, and Tang, and topic 2009; important, Rajendran particular Annaert, this similarly on routing. and reviews are recent their (Sannerud this several cell to to for referred the is secretases reader essential in direct are location that destined that pathways protein regulatory Obviously, this of properties rvreteGliadTNt h lsammrn hr otprecursor most where membrane plasma by the cleaved to are TGN molecules and Golgi cells. the in traverse trafficking APP 1. Fig. B A el yteie P oeue olwteconstitutive the follow molecules APP synthesized Newly b and - elsurface cell xotto Export α B LRP1B nenlzto fAPi otoldb Rs ru fendocytic of group a LRPs, by controlled is APP of Internalization ) c endocytosis sceae ( -secretases Delay of APP α ? APOER2 F-spondin b rnpr oTGN to transport TGN Fe65 , a c Retrograde sceae( -secretase sblee opoedi nooe n nthe in and endosomes in proceed to believed is ) endosome Early Early ( A el yteie P molecules APP synthesized Newly ) β a APP b .Nnpoesdprecursors Non-processed ). γ endosomes Early Clathrin ycnrs,bnigt h slow- the to binding contrast, By . endosomes Early AP2 β aiiainof Facilitation β endocytosis γ Fe65 endosome Late γ aeendosomes late rnpr to Transport LRP1 Clathrin-mediated β endocytosis γ - Golgi a . Journal of Cell Science h elsraetruhcahi-eitdendocytosis. cytoplasmic clathrin-mediated the in motif through NPxY an by surface guided is plasma Internalization cell the by internalized At are the and processing 2012). non-amyloidogenic by this sAPP escape al., cleaved soluble are et molecules release Haass APP most in membrane, (reviewed sulfation including eefml,teLLrcpo-eae rti LP) This (LRP1). 1 protein receptor-related LDL the receptor (LDL) an family, APP with low-density interaction internalizing the its of of through receptor modulated efficiency endocytic is surface the cell amyloidogenic the the Thus, of from raised regulation 1B). the of studies (Fig. for co-receptors these transport on depends pathway, efficiency APP endocytic that awareness the the that in notion breakdown determines the a substantiating is Vos amyloidogenic endocytosis from endocytosis APP De Apart of enhanced 2006; regulation process. the Cataldo, well-studied instance, of and For 2008). (Nixon trafficking al., causative AD et neuronal sporadic be the in in processing defects elucidating might of that because on least processes showed the focused that not transport, observations have APP control proteolytic that studies mechanisms for trafficking many intracellular processing, of importance APP of the internalization Given the modulate receptors Endocytic axons along 2007). normally al., sorted et still (Back lack dendrites Apparently, require are that and tail not 1995). mutants cytoplasmic does APP al., entire because neurons the signals, et polarized sorting in Haass basolateral APP these 1995b; type) of cell al., transport renal axonal et (a cells Strooper identified kidney APP been AD canine of (De have Darby tail sorting in Madin the basolateral polarized in seen its in sequences for peptide as important Two processing are 2008). APP, the that amyloidogenic al., its of et on aggravate Vos transport and Muresan, (De to likely axonal 1990) and an are al., in pathology, (Muresan both et Defects kinesin-1 in (Koo protein 2005). the system motor sorted on depends 1995; transport microtubule APP al., be of et axonal transport Simons to Axonal 1995a; fast 1995). al., al., et dendrites fate et Strooper and De Yamazaki axons intraneuronal 1990; its along al., et manner to is (Koo retrograde a unique the APP and anterograde However, and of endocytic types. 2011) trafficking of 1999). cell case al., al., et the non-neuronal (Vassar model in et 2000; this (as support al., Sannerud activity milieu its acidic for et 2002; vesicles) an of (Huse al., of localization requirement compartments et predominant endosomal The Pastorino to 2008; 2011). 1992; al., et al., al., secretase Rajendran by et 1996; et Haass al., et or 1992; Sannerud Ikin al., 1994; et 1999) Squazzo, (Golde and in Koo endosomes al., proceeds late processing or amyloidogenic et early that suggest (Perez studies by Most impairs motif endocytosis mutants dynamin NPxY APP A dominant-negative of of its overexpression amyloidogenic blocking of to example, subjected deletion is For molecules processing. APP fraction endocytosed this the that the of suggests to to evidence retrogradely moves experimental or Extensive al., typically compartment, TGN. et APP lysosomal or (Boll endosomes, endosomal AP2 early late their complex the facilitates adaptor From and clathrin 2002). receptors the This endocytic 1997). with many al., interaction in et Marquez-Sterling found 1995; is al., motif et (Lai APP of tail b h aha ecie bv ple obt ernland neuronal both to applies above described pathway The rdcin(hugadSlo,20;Crye l,2005). al., et Carey 2003; Selkoe, and (Chyung production N and - O lne lcslto,popoyainand phosphorylation , -linked a oee,sm rcro molecules precursor some However, . a sceaeto -secretase b - o ta. 06.Rcnl,teF6-eitdinteraction Fe65-mediated the Recently, 2006). in al., decrease a LRP1B et and or surface Because Hoe cell APOER2 the with present. on APP A sequestration at compared of its endocytosed in interaction association unclear results slowly of the more is mode LRP1, are The with APP LRP1B 2006). and the al., and APP APOER2 et between and LRP1B Hoe APOER2 complex 2005; between of al., the et domains of F-spondin, (Hoe extracellular , formation and extracellular the cytoplasmic an al., mediates et through Hoe which and both 2005; proceeds al., Fe65 APP et and Hoe through APOER2 2005; between two LRP1-induced al., 1B) interaction et The (Fig. LRP1B, Cam 2006). E binding 2004). and 2004; APP al., for apolipoprotein LRP8) et LRP1 mouse (Cam as al., with by compete in known that counteracted LRPs also et and related (APOER2, 2005) is 2 (Zerbinatti al., APP receptor et AD of Cam 2000; internalization accelerates of al., 2004). surface et cell models al., (Ulery the A cells et enhances at and in trimeric protein, Pietrzik LRP1 precursor a the with 1998; of forming endocytosis APP LRP1 al., of and et Interaction APP (Trommsdorff of motifs tails complex NPxY cytoplasmic to binds the (also simultaneously Fe65 in which protein APBB1), adaptor as cytoplasmic known the involves interaction rcs hti fpriua eeac o D(e o for 2 Box (see AD for 2013). relevance Westmark, particular This 2002; of (Selkoe, APP. is details) activity, synaptic of that a to process APP internalization create of a processing to the the believed link drives might is mechanism that vesicles, shunt synaptic results of membrane which recycling turnover, the membrane here, from ; the at proceeds Wagner 2009; Herz, 2009; (Bu, 2012). to topic Pietrzik, referred and this is reader on the al., reviews progression, the excellent AD of et density for discussions in-depth LRPs (Alvira-Botero very-low more of For implication reported the 2012). al., been et and Dumanis 2010; has (LRP2) family gene receptor, megalin receptor lipoprotein namely LDL the APP, of and receptors further two between ta. 94.Aatfo OL,fu diinlVPS10-domain additional (Marcusson four vacuole SORLA, directs from the Apart that to 1994). receptor TGN al., yeast et the the domain from in VPS10 binding hydrolases The ligand lysosomal yeast. of in site receptor the also sorting forms protein, a 10 The initially Pep1), sorting was as protein 2008). which known vacuolar (the members, al., VPS10 family in in et all found identified of module (Willnow acid part amino extracellular 2A) 700 a the (Fig. from derived from man is of domain conserved family VPS10 to a are of yeast member which a baker’s receptors, (Jacobsen and 1996) protein VPS10-domain al., sorting-related transmembrane et so-called Yamazaki type-1 SORLA). or 1996; kDa as al., AD 230 SORL1), to et orphan a referred as sporadic the is (hereafter are SORLA repeats was known A-type that genes from with (also these receptor genes Amongst suffering LR11 colleagues identify 2004). receptor al., and patients to et this Lah (Scherzer profiling in by answering expression observation towards downregulated used processes an hint AD-related from who first for came the relevance The question their intuitive, enigmatic. and and appeared to remained TGN, particularly internalization cells, the within its APP from sort of might receptors that endocytic control mechanisms and the APP between for AD interaction in the implicated receptor Although trafficking neuronal a SORLA, b natraiepoesta ouae h noyoi fAPP of endocytosis the modulates that process alternative An rdcin(ie l,20;Cme l,20;Hee l,2005; al., et Hoe 2004; al., et Cam 2001; al., et (Li production OL otostafcigo P 2753 APP of trafficking controls SORLA b production Journal of Cell Science ssonb h oso G oaiaini eetrmutants receptor in localization TGN of loss the the domain, to receptor by cytosolic SORLA the shown in of motifs as LDL targeting sorting by Retrograde the guided surface. is endosomes TGN as cell early the from such to recycle typically back receptors, 2007) which LRP1, al., clearance apart or SORLA et receptor prototypic sets Schmidt behaviour other trafficking 2007; from distinct al., and This TGN et 2B). between (Fig. (Nielsen shuttle to endosomes continues 2007) early to thereafter, al., retrogradely and, et moves TGN Nielsen SORLA the endosomes, 2001; early al., SORLA, From et 2B). of (Jacobsen (Fig. AP2 tail to cytoplasmic binds the which an al., in by mediated et site is ( Offe that acidic-cluster-dileucine internalization membrane 2001; rapid plasma exhibit al., mass) the et early receptor at (Jacobsen in Receptors TGN found the 2006). predominantly in is At and SORLA 1999). endosomes al., level, et subcellular (Motoi cerebellum the and cortex, the 2A). (Fig. LRPs by shared for are modules which structural interactions, additional protein–protein because contains neuronal receptors, region these extracellular 2008). distinct amongst its al., unique et are is (Willnow SORLA members there Structurally, are family various that receptors the for suggesting and functions vertebrate peripheral and 2001) systems, All central the al., of nervous 2001). populations et cell al., defined (Rezgaoui in expressed et SORCS2 (Hampe 1999), SORCS3 al., (SORCS1) et 1 (Petersen expressed sortilin (Hermey CNS receptor designated sortilin-related 1997), vertebrates, al., in et found are receptors 2754 o yatcatvt.Tefloigmdlhsbe rpsdto proposed been A and has activity synaptic model between link following a The explain loop activity. negative-feedback synaptic a providing for apparently 2008), al., et Cirrito rmtesraeo yatctriiit nooe,thereby endosomes, into termini molecules synaptic A APP of of shunts production pre- inducing that surface the flow at the vesicles membrane from synaptic a of creates membranes synapse the of recycling and important brain the an in and is 2003) activity al., et synaptic (Kamenetz A model, synaptic for this This force of of driving 2006). suppression support In aberrant al., brain. A that excessive et by and caused is transmission Hsieh activity A for synaptic 2005; role of physiological al., a plasma suggests synaptic et observation the (Snyder from receptors membrane glutamate of internalization lgmrcfrso A of forms Oligomeric APP and of trafficking processing activity-dependent Synaptic 2. Box nteban xrsino OL swdsra nnuosof neurons in widespread is SORLA of expression brain, the In yatcvesicles synaptic ora fCl cec 2 (13) 126 Science Cell of Journal okn of Docking b rdcin ohi ipcma lc cultures slice hippocampal in both production, vesicle Synaptic Endosomes b b the inducing by plasticity synaptic impair sefgr)(irt ta. 2008). al., et (Cirrito figure) (see A β APP b rdcini h diseased the in production nvivo in Production of Membrane b recycling A rdcin docking production: Crioe l,2005; al., et (Cirrito β , b 0 ftetotal the of 10% samodulator a as ofr h soito fsnl uloiepolymorphisms 2011) nucleotide al., single et Naj of 2007; in association (SNPs) al., genome- et the and 2011) (Meng confirm al., studies et association (Reitz 2008; individuals encompassing wide al., 30,000 meta-analyses et of Lee Cumulative excess 2008; 2008). in al., al., et et Cuenco al., 2008; Webster et al., (Rogaeva et ethnicities Bettens several 2007; in AD sporadic with SORLA) cooanwr bevdi h eersia li fAD of fluid cerebrospinal the in observed were ectodomain 2007). al., autopsy et (Sager individuals Subsequent in impairment in 2004). cognitive expression noted mild al., receptor with et poor previously documented (Scherzer also been patients studies AD affected have not from is pathology), material that tissue and AD AD-related (a cortex cerebellum by in in in SORLA not of but receptor levels hippocampus, reduced trafficking instance, For presumed processes. studies this genetic and implicated pathophysiological from evidence enigmatic, sorting line-derived intracellular neurons. and/or physiological cell in the uptake was platelet- represent SORLA-dependent it ligands of and However, these targets 2004). of 2011), 2004) al., any whether et al., al., unclear (Gliemann et factor et growth (Westergaard derived including Klinger factor SORLA, 2001; neurotrophic (Jacobsen of al., lipoprotein region 2001), et ligands al., al., et extracellular of et (Taira number E Morinville the A apolipoprotein 2008). 2001; sortilin with al., al., al., for et interact et (Nielsen et described SORCS1 Nielsen Schmidt and been 2001; 2004) 2007; have al., al., et paths et (Jacobsen sorting (Nielsen Similar domain 2007). tail the lacking soito fgntcvrat of document variants that genetic studies of population-based sporadic Nevertheless, from association in SORLA issue. stems of which this involvement the AD, resolve for support to additional strong is therefore, necessary there and, be 2012), might al., post-mortem et of studies (Sager set al., the samples another et recapitulate yet brain to Sager in AD failed al., SORLA 2006; study of recent et al., expression A et reduced (Scherzer 2007). al., Dodson AD et 2005; Zhao sporadic al., 2007; with et Andersen individuals 2004; some of brain an reported disease. of cause this primary of a form constitutes sporadic probably the AD of non-familial SORLA consequence in of secondary seen expression a poor just Rather, not 2006). processes. is al., neurodegenerative receptor et is this (Dodson of SORLA FAD loss of from Thus, expression suffering AD, individuals sporadic in of In normal parenchyma. cases brain some the the for to in indicative expressed contrast 2B). receptor is intact that (Fig. the biomarker present of a levels at as considered unclear is is it However, ectodomain of SORLA significance pathophysiological soluble The the 2009). al., et (Ma patients gis D–ahptei hti nln ihterdcdlevels reduced the protecting with line factor in a is that the as hypothesis perceived a reduced was – AD receptor in against the SORLA it, increased of A of overexpression production Because in processing and brain is 2005). trafficking mouse SORLA the its in affect that and to found cells and cultured collaborators APP, to our bind in and to SORLA able we of when involvement came the AD understanding in processing breakthrough and A trafficking APP controls SORLA utemr,dcesdlvl fteseddSORLA shedded the of levels decreased Furthermore, remained initially neurons in SORLA of role the Although otsuiso ri rcrbopnlfudspecimens fluid cerebrospinal or brain on studies Most SORL1 , 05%dces ntelvl fSRAi the in SORLA of levels the in decrease 20–50% b hra oso OL xrsini mice in expression SORLA of loss whereas , ihAD. with SORL1 nvivo in el Adre tal., et (Andersen cells tegn encoding gene (the Journal of Cell Science rcsigo P Adre ta. 05 fee l,2006; 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(Schmidt the ability (Fig. are the which APP blocks homodimers, SORLA for form with factor interaction retention the SORLA TGN model, that instead a assumes hypothesis as but first functions The APP activities, 2012). substrate al., their secretase et of binding (Schmidt inhibit been through effects has inhibitory directly SORLA its addition, exerts not In 2012). to al., et shown Schmidt 2007; al., et oetal eesr o fiin xto P rmteTGN. the from APP of exit efficient are for post- that necessary its processes potentially impair formation, might dimer or SORLA modifications and translational TGN APP Alternatively, the between unknown. interaction by is the SORLA mechanism Banfield, similar of and a retention short- through (Tu operates the of domains whether several cytoplasmic presence However, their 2010). 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A pharmacological of by kinases production these or of activity the knockdown amyloidogenic of in inhibition implicated because been 2011), processing, al., previously et have Herskowitz (rho-activated that 2010a; al., ROCK2 enzymes et and (Lane 2) C kinase receptor kinase coiled-coil the protein in intracellular by regulator soluble phosphorylated transcriptional a a (Bo as in nucleus function might results as Nyborg that act but 2006; domain to SORLA al., of factor, ability et the sorting intramembrane can Hermey abrogates Proteolysis SORLA 2000; 2006). regulated that al., al., et known and et is (Hampe It shedding of proteolysis APP. sort ectodomain ability and the undergo to modulate bind to also SORLA might 2013; al., modifications et translational Gustafsen 2011; clarification al., 2013). further et al., Finan et warrant 2010b; Lane al., mechanisms et underlying APP (Lane of the trafficking a additional but the or this in and of of functions roles factor and exclusive, molecular the similar exact retention Recently, mutually the Obviously, elucidate anti- receptor. a to not required an model. as are are as studies SORLA latter receptor act for the still sorting functions might in proposed SORLA factor 2006), (Schmidt al., amyloidogenic Because of APP et access amyloidogenic 2012). of the the (Spoelgen impairs al., dimerization and the deliver et facilitate 2012) al., inhibits Choy et would SORLA 2010; SORLA- that to al., therefore, APP binding et compartments and (Burgos of breakdown TGN, to sorting the precursor retrograde in place dependent takes cleavage 2172 ae oehr h vial aaspotamdli which in model a support data available the together, Taken nadto oitrcin ihctslcaatr,post- adaptors, cytosolic with interactions to addition In NH oi Saa,20;Saa,20;Fjorback 2007; Seaman, 2004; (Seaman, motif ANSHY b sceaehv ensgetdfrsrii n SORCS1, and sortilin for suggested been have -secretase h ta. 06 Fg B.I diin OL is SORLA addition, In 2B). (Fig. 2006) al., et ¨hm b Zo ta. 03 ectnegre al., et Leuchtenberger 2003; al., et (Zhou c aatnerhmlg oan ARF- domain, homology ear -adaptin dposGA,GA n GGA3 and GGA2 GGA1, adaptors h eil ot agt the targets coat, vesicle the f b sceaet t substrate its to -secretase b nassumption an – 2207 DVPMVIA b -secretase Journal of Cell Science OL ih ersn a nwiht euaereceptor regulate 2B), (Fig. to sorting which anterograde control in and way GGA with a interaction of represent phosphorylation might Conceptually, 2010). SORLA close of al., been et has tail in (Cramer GGA serine-2206 of in reported cytoplasmic phosphorylation increase found upon sixfold the SORLA A to 2012). in residue binding al., site et a (Herskowitz GGA-binding receptor the serine-2206, the to at proximity occurs primarily eei ikfcosi D oeot hsapist the to applies VPS35, this of composed that Foremost, is surprise AD. which no complex, in as as retromer comes factors emerge pentameric it machinery risk trafficking APP, this genetic of of trafficking components additional the of in loss role associated downstream a the that through unknown possible deleterious the to is SORL1 is insults yet chronic It system, in shown 2009). as nervous neurons, and al., to support et trophic extracellular-signal-regulated poor (Rohe pathway factors the transcription (ERK) through 2003). tenfold the kinase (Chao, of than neurons growth transcription to more a activates support potently (BDNF), trophic BDNF factor provides be neurotrophic that might the factor brain-derived in the low levels is SORLA modulates that are that brain of protein arguing Another levels induction 2007). al., in models, DHA et defects mouse when by in risk explained and disease SORLA of neurons increased expression 2006). upregulate primary Schaefer, markedly in and to (Johnson shown study was DHA epidemiological neurodegeneration large of risk a DHA increased of in an levels with blood associated low been because AD, have in implicated been dietary has docosahexaenoic that essential is factor an such (DHA), One acid 2007). al., et (Rogaeva brain less 60% uncovered AD. amyloidogenic sporadic increased of to causative is hence, that and, processing activity individuals genetic receptor cellular the predispose low the concerns that to in question mechanisms SORLA important pathophysiological an and implicates APP, that of evidence processing AD the sporadic all underlie might Given activity SORLA of Loss ROCK2 how for explanation A influences mechanistic activity a providing thereby aitosol con o sltl s1%o aitosin variations of 14% modulate as factors non-genetic little or genetic as for SORL1 account only variations in seen 2012). reduction al., the et to (Caglayan similar patients in is less reduction AD which 30% are levels, a cultured in protein transcripts result in SORLA and SNP-containing studies protein into Further these translated efficiently genotype. that the SNP confirmed in the the cells of in receptor sequence usage the the codon alter of variations expression the gene SORL1 These identified low brain. we 3 with diseased the Recently, in correlate 2009). SNPs linked al., which closely et two 5 of (Grear the presence AD in of SNP a cases of of levels presence lower colleagues the between sequence and correlation Grear that a assumption, this found proposed with accordance been In 2004). has it in variations controls, with compared eas eeepeso rfln nlmhbat has lymphoblasts in profiling expression gene Because eas OL n t neatn dposhv pivotal a have adaptors interacting its and SORLA Because oee,rgeso nlsssgetdta sequence that suggested analyses regression However, rncit n euti hnefo rqett rare a to frequent a from change a in result and transcript, xrsin(arn ta. 08 oee l,2009). al., et Rohe 2008; al., et (Matrone expression RAlvl,adteeoeidct htadditional that indicate therefore and levels, mRNA SORL1 ih fettasrp ees(cezre al., et (Scherzer levels transcript affect might b levels. SORL1 9 v nrncrgo ftegn in gene the of region intronic rncit nA patients AD in transcripts 3plustrtdftyacid fatty polyunsaturated -3 SORL1 SORL1 SORL1 9 rncito (Ma transcription einof region xrsini the in expression SORL1 RAand mRNA eeby gene SORL1 , lno,K,d en .J n etreg H. Zetterberg, Broeckhoven, and J. Van M. Leon, P., de P. K., Blennow, Deyn, De S., Engelborghs, N., Brouwers, K., Bettens, ak . as . Tscha P., Haas, S., Back, nesn .M,Shit . pegn . lean . ele . aai,D., Galatis, J., Behlke, J., Gliemann, R., Spoelgen, V., Schmidt, M., O. Andersen, erts ciiis–apoesta a rvosypoorly previously was that process a various – the harbour of activities In that transport compartments targeted secretase neuronal the patients. on distinct unique light to a sheds APP in SORLA, APP, for of receptor processes characterization cellular sorting functional neurodegenerative of the they how particular, elucidation and to processing, detailed APP contribute control the that pathways witnessed trafficking years Recent Conclusions dysfunction. of neuronal transport of cause anterograde additional impaired an that is the suggesting SORLA Moreover, 2007), 2011). enhances al., al., expression et et GGA3 a (Santosa brain of in patients In loss observed AD 2000). are of GGA3 al., of autopsies levels et decreased al., (Nothwehr manner, et similar cause processes (Fjorback underlying an neurodegenerative APP be of might of function, processing retromer by impaired for mediated 2012), is important which dysfunction, is SORLA, synaptic of retromer, transport and retrograde A As deficits elevated 2008). memory with associated in in are of which disruption (reviewed the results and in 2005), 2 mice al., expressed et and in poorly (Small patients 1 are AD VPS26 of nexins brain and sorting VPS35 2012). the Seaman, and VPS26 VPS29, imre o igoi,adprasi ih vncnttt a AD. new constitute of and it even treatment factor might the pathway, for it risk sorting target perhaps genetic druggable this and a diagnosis, about as for learned promise biomarker in missense great be domain Although holds to AD. binding five certainly of needs APP cases Here, still the familial in much to 2012). identified maps been al., have which SORLA, of et one (Pottier mutations, in AD in receptor mutations early-onset that this report of recent a role SORL1 is exciting crucial Equally AD. the sporadic substantiate epidemiological further and studies histopathological from Results understood. nesn .M,Rih,J,Shit . otad,M,Sole,R,Bhk,J., Behlke, R., Spoelgen, M., Gotthardt, V., Schmidt, J., Reiche, M., O. Andersen, Pe X., Alvira-Botero, O.M.A. References to Foundation O.M.A.] Danielsens to Ejnar 11-4408 and the number Aase [grant the T.E.W.]; Foundation and the O.M.A.]; Augustinus to to O.M.A.]; R179-A15311 the to number 11810 and [grant R93-A8578 Foundation AFI number Nordisk Alzheimer Thyssen Novo [grant number the Fritz Foundation T.E.W]; [grant the Lundbeck to Initiative T.E.W.]; 10.11.1.226 to Research number HA-215 [grant Helmholtz-Association number Foundation the from [grant grants by (HelMA) supported was work This Funding aeostazemrdsaei h ega population. Belgian the in disease alzheimer late-onset K. Sleegers, and C. 368 compartment. dendritic and axonal the to signal sorting Res. Neurosci. any J. S. of Kins, independent and K. oeua iscino h neato ewe mli rcro rti n its al. and et protein T. precursor B. amyloid Hyman, between SorLA/LR11. L., receptor interaction C. trafficking the Masters, neuronal of W., M. dissection Parker, Molecular J., W. 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