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Biological function of Presenilin and its role in AD pathogenesis Zhang, Shuting; Zhang, Mingming; Cai, Fang; Song, Weihong Jul 17, 2013

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REVIEW Open AccessBiological function of Presenilin and its role in ADpathogenesisShuting Zhang, Mingming Zhang, Fang Cai and Weihong Song*AbstractPresenilins (PSs) are the catalytic core of γ-secretase complex. However, the mechanism of FAD-associated PSmutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of γ-secretaseand focus on the catalytic components – presenilins and their biological functions and contributions to the ADpathogenesis. The functions of presenilins are divided into γ-secretase dependent and γ-secretase independent ones.The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing ofAPP and Notch; the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signalingpathway, regulating calcium homeostasis and their interaction with synaptic transmission.IntroductionAlzheimer’s disease is the most common neurodegenera-tive disorder leading to dementia, accounting for twothirds of dementia in elderly populations. The majorityof AD cases are late-onset and sporadic without definedcauses, whereas less than 5% of cases are familial withearly-onset and caused by gene mutations. Genetic stud-ies have shown that four genes confer susceptibility toAD: amyloid-β precursor protein (APP) on chromosome21 [1-6], Presenilin 1 (PS1) on chromosome 14 [7-10],Presenilin 2 (PS2) on chromosome 1 [11-13] and apoli-poprotein E (ApoE) on chromosome 19 [14,15]. Neuriticplaques, neurofibrillary tangles (NTFs) and neuronal lossare pathological hallmarks of AD. However, the mechan-ism underlying AD pathogenesis remains elusive andthere is no effective prevention or treatment to this dev-astating disorder so far.Neuritic plaques are formed by extracellular deposits ofamyloid β protein (Aβ) [16]. Aβ is derived from proteolyticprocessing of APP and consists primarily of 40- and 42-amino acid residues, with the more hydrophobic Aβ42 asthe major component in neuritic plaques [16,17]. NFTs areintraneuronal inclusions composed of hyperphosphorylatedforms of the microtubule-associated protein Tau [18-21].Aβ-containing neuritic plaques are the unique pathologicalfeature in AD brains whereas NTFs could also be detectedin other dementia subtypes like frontotemporal dementiawith Parkinsonism caused by mutations on MAPT gene[22]. Current prevailing “amyloid hypothesis” in AD sug-gests that the accumulation of Aβ, particularly the morehydrophobic and aggregation-prone Aβ42, being solubleoligomers [23-29] or aggregate fibril form, initiates neuronaldysfunction, resulting in neurodegeneration in AD [30].The central event of “amyloid hypothesis” is APP pro-cessing. APP undergoes posttranslational proteolytic pro-cessing by α, β and γ-secretases (Figure 1). The majorityof APP is constitutively processed by α-secretase withinthe Aβ domain in a non-amyloidogenic pathway [31]. Inthe amyloidogenic pathway, APP undergoes sequentialcleavages by β- and γ-secretase to generate Aβ. A trans-membrane aspartic protease BACE1 was identified asβ-secretase [32-35]. BACE1 processes APP at the Asp1site of Aβ domain to generate APP C99 fragment [34,36].The C99 fragment is further processed by γ-secretase atthe intramembrane Val40 and Ala42 sites to generate Aβ40and Aβ42, respectively. The second cleavage, which takesplace within the hydrophobic transmembrane domain(TMD) and is termed as regulated intramembrane prote-olysis (RIP) [37], has been attributed to γ-secretase withpresenilins as the catalytic component [38-45].As the catalytical component of γ-secretase, the first partof this review will focus on the contribution of presenilinsto γ-secretase and its role in AD pathogenesis in the sce-nario of “Amyloid hypothesis”. The rest of this review willdiscuss diverse biological functions of presenilins inde-pendent of γ-secretase activity. Its well-established role in* Correspondence: weihong@mail.ubc.caTownsend Family Laboratories, Department of Psychiatry, Brain ResearchCenter, Graduate Program in Neuroscience, The University of BritishColumbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, CanadaTranslational Neurodegeneration© 2013 Zhang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Zhang et al. Translational Neurodegeneration 2013, 2:15http://www.translationalneurodegeneration.com/content/2/1/15β-catenin/Wnt-signaling and calcium homeostasis as wellas the contribution to the AD pathogenesis will beaddressed.Presenilins and γ-secretasePresenilinsPresenilins have two homologs, PS1 and PS2, with 67%identical sequence [11]. mRNAs of both Presenilins areubiquitously detected in many human and mouse tis-sues, including brain, heart, kidney and muscle [46]. PS1and PS2 are highly conserved and functionally redun-dant with SEL-12 as their homolog in Caenorhabditiselegans [47].PS1 is a multi-transmembrane protein with nine-transmembrane topology (Figure 2) [48,49], andabundantly present in the ER and trans-Golgi net-work [50-53]. Under physiological condition, the ma-jority of PS1 undergoes endoproteolysis within thelarge hydrophobic loop in the cytoplasmic side togenerate N-terminal fragment (NTF) and C-terminalfragment (CTF) [54]. The endoproteolytic cleavagetakes place at heterogeneous sites from amino acid292 to 299 [55-57]. While some studies reported anindependent protease as the “presenilinase” [58,59],growing evidence supported the hypothesis that PS under-goes autoendoproteolysis [43,60-64]. The endoproteolysisevent might be important to render the γ-secretase activ-ity to PS NTF/CTF heterodimer by removing the auto-inhibitory effect of the large hydrophobic loop [64,65].However, it is not clear whether endoproteolysis is an ab-solute requirement for the maturation of presenilins sincesome presenilin mutants are enzymatically active in theabsence of endoproteolysis, as are the cases in FAD-associated PS1ΔE9 and PS2 M292D [57,66].γ-Secretase complex assemblingγ-secretase is essential for cleavage of APP C99 to gener-ate Aβ [67]. γ-secretase is a multi-unit enzymatic complex,including presenilin NTF/CTF heterodimer, nicastrin,Aph-1 and Pen-2 [39,41-45]. Presenilins are the first mole-cules identified to be associated with γ-secretase in vivoand in vitro. PS1 knockout mice showed markedly re-duced γ-secretase cleavage of APP [38] and knockout ofboth PS1 and PS2 completely abolished γ-secretase activ-ity [40,68]. Using anti-PS antibody, Yu et al. identifiedNicastrin, an integral transmembrane protein with a largeN-terminal domain, as the second γ-secretase component[39]. However, expression of both presenilins andnicastrin don’t suffice to restore γ-secretase activity, indi-cating the existence of other components. Further genescreening studies on the glp-1 (Notch homolog) deficientphenotype of C.elegans discovered Aph-1 and Pen-2as another two components of γ-secretase [41,42].Aph-1 is a 30 kDa multi-transmembrane protein likepresenilin, whereas Pen-2 is a 12 kDa hairpin-liketransmembrane protein. Co-expression of presenilin,Aph-1, Pen-2 and nicastrin increases γ-secretase activ-ity in transfected cells and the four proteins togetherFigure 1 APP processing pathways. Under the physiological conditions, the majority of APP undergoes the non-amyloidogenic pathway. Theα-secretase processes APP within the Aβ domain to generate C83 and this cleavage abolishes Aβ generation. In the amyloidogenic pathway,β-secretase processes APP at Asp1 site to generate C99 fragment, which is the substrate for γ-secretase for Aβ generation.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 2 of 13http://www.translationalneurodegeneration.com/content/2/1/15are sufficient to reconstitute γ-secretase activity inyeast [44,69].Previous studies demonstrated that the minimal mo-lecular weight of γ-secretase complex was around 200–250 kDa, implying a 1:1:1:1 stoichiometry of PS/Nicastrin/Aph-1/Pen-2 in γ-secretase complex [44].Though it was accepted that the four molecules werethe minimal γ-secretase complex assembling, recent re-port suggested that the PS/Pen-2/Aph-1 complex wassufficient for the catalytic activity in the absence ofNicastrin [70]. Another study demonstrated that PS1ΔE9alone had partial γ-secretase activity and PS1ΔE9/Pen-2was sufficient to restore full γ-secretase activity [71].These studies suggest the complexity of γ-secretase com-plex assembling. Given the stoichiometry of γ-secretasecomplex and the existence of PS and Aph-1 homologs,there are at least six different forms of γ-secretasecomplex that could be assembled [72,73]. PS1-involvedcomplex or PS2-involved complex processed APP C99differentially and showed distinct susceptibility to cer-tain γ-secretase inhibitors [74,75], indicating differentγ-secretase complexes with possible distinct functions.Structure of γ-Secretase complexThe catalytic core of γ-secretase complex is presenilins.Presenilins, together with signal peptides peptidases(SPPs), belong to aspartyl intramembrane cleaving prote-ases (I-CLiPs) [76]. The two catalytic aspartate residues(Asp257 in transmemberane 6 (TM6) and Asp385 in TM7)are located at NTF and CTF of presenilins, respectively.Mutations on either aspartate abolish the enzymatic activ-ity of γ-secretase complex [60]. With a large highlyglycosylated ectodomain, nicastrin has been implicated tofunction as the initial recognition of substrates [77]. Elec-tronic microscopic analysis and single particle imaging re-vealed the existence of intramembrane water-accessiblecylindrical chamber in gamma-secretase with a low-density cavity from extracellular side [78,79]. Parallelsubstituted cysteine accessible method (SCAM) andcross-link experiment confirmed that TM6, TM7 andTM9 of PS formed the intramembrane chamber with twocatalytic aspartates residing oppositely on TM6 and TM7,respectively [80-84]. The constitutive autoendoproteolysisof PS removes the inhibitory allosteric effect of thelarge hydrophobic loop from the catalytic chamberstructure in PS [64,65]. With direct interaction be-tween γ-secretase components [85,86], Nct/Aph-1 sub-units and Pen-2 tighten the relative loose PS TM6/TM7/TM9 intramembrane cavity and rearrange the PALPmotif of TM9 to the proximity of the catalytic center, thusactivate the γ-secretase complex [87] (Figure 3). Recently,Li et al. reported the crystal structure of a presenilin/SPPhomologue (PSH) from the archaeon Methanoculleusmarisnigri JR1 and predicted the structure of presenilinbased on the conserved sequence between the two homo-logues [88]. They confirmed the existence of the waterFigure 2 Presenilin 1 structure. This diagram shows the amino acid sequence of PS1 and the distribution of the FAD-associated mutations.Blue circles represent the FAD-associated mutations and red circles indicate the two catalytic active aspartates.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 3 of 13http://www.translationalneurodegeneration.com/content/2/1/15permissible cavity but also revealed some differences inTM7 and TM9 compared with the NMR structure of PS1CTF. The work shed new light on elucidation of the crys-tal structure of presenilin.γ-Secretase substrates and sequential cleavagesAPP and Notch as classical substratesγ-Secretase preferentially processes type I integral mem-brane protein after the ectodomain is shedded [89]. It is in-triguing that many of its classical substrates function in thesignaling pathways, cell adhesion and migration, neuritisoutgrowth and synapse formation, and many of these eventsare often disrupted during AD pathogenesis [90]. The num-ber of substrates is growing to over 80, including APP,Notch, neuregulin, ErbB4, E-cadherins and N-cadherins,CD44 and growth hormone receptor [40,91-98].APP and Notch are two most well known γ-secretasesubstrates. γ-Secretase is named after it function as theenzyme to process APP at the γ-cleavage site to generateAβ, which is currently believed to play an essential rolein the “Amyloid cascades” in AD pathogenesis. Notch isa type I transmembrane cell surface receptor that medi-ates cell fate decisions in both vertebrates and inverte-brates [99,100]. After it is cleaved by furin, cell surfaceNotch receptor heterodimers bind to the DSL (Delta/Serrate/LAG-2) family ligands on the surface of neigh-boring cells, then the transmembrane-intracellular frag-ment of Notch undergoes further proteolysis to releaseNotch intracellular domain (NICD) from the membraneto the nucleus to activate target genes [101,102].Presenilins have been shown to play an essential role inNotch signaling. PS-deficient mice exhibit Notch-knockout phenotype [103,104]. Knockout of PS abolishesintramembrane γ-secretase cleavage of Notch as well asthe following release of NICD [40,91,105], and FAD-associated PS mutations impair the generation of NICD[91]. Although it is reported that the impaired Notch-signaling is involved in synaptic plasticity and late-onsetcognitive decline [106-110], the contribution of Notch-signaling to AD pathogenesis remain to be elucidated.γ-secretase cleavages at ε-site and γ-siteγ-Secretase can process substrates at multiple cleavagesites. γ-secretase cleaves the transmembrane domain ofAPP at two positions: the γ-site to generate Aβ and thedownstream ε-site to produce the APP intracellular do-main (AICD) [111]. Cleavage at the γ-site is heteroge-neous, producing Aβ of 39–43 residues, whereas thecutting at the ε-site produces AICD of 50 residues al-most exclusively. The same phenomenon occurs inNotch processing: heterogeneous cleavages at the S4 site(γ-site) to generate Nβ and homogeneous cleavage at theS3 site (ε-site) to generate NICD [112]. Recent inde-pendent studies supported the notion that the ε-cleavageoccurs prior to γ-cleavage [113-115]. Qi-Takahara andcolleagues first detected Aβ49, the proteolytic counter-part to AICD50-99 [113]. Later Ihara and colleagues dem-onstrated that ε-cleavage occurs first and produces Aβ48and Aβ49 for later γ-cleavage, based on the presence ofthe induction period for the generation for tripeptides/tetrapeptides detected by liquid chromatography tandemmass spectrometry (LC-MS/MS) in cell-free γ-scretasesystem [116]. The various Aβ species (ranging from 49- to40-amino acids) and corresponding tripeptides releasedfrom the trimming of Aβ48/49 were identified using LC-MS/MS, further confirming the sequential γ-cleavagefrom the ε-site to γ-site [113,116,117].The effect of FAD-associated presenilins mutations on γ-cleavagesPresenilin mutations are the main cause reasons ofearly-onset FAD. Presenilin mutations result in the pro-duction of the more hydrophobic Aβ42 either in condi-tioned medium in vitro assay [67,118] or in APP/PS1transgenic mice [119]. It still remains elusive how PS1mutations affect the enzymatic activity on ε- and/or γ-siteto initiate the AD pathogenesis. Considering the signifi-cant role of Notch in neurogenesis and impaired Notch-signaling in the scenario of presenilins mutations, thecontribution of Notch signaling has always been a de-bating topic in AD field.Figure 3 γ-secretase complex and the formation of the catalytic pore of PS1. PS1 transmembrane domains (TMDs) are shown as columnswith numbers. Without the assistance of other subunits, PS1 forms a relatively open pore structure within the membrane. Upon the binding ofsubunits, the PALP motif moves to the proximity of the catalytic center, and the catalytic structure is activated by the structural changes in TMDsof PS1.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 4 of 13http://www.translationalneurodegeneration.com/content/2/1/15γ-Secretase processes its substrates at γ- and ε-site,generating distinct products exemplified as Aβ andNICD. Aβ plays central role in AD pathogenesis;whereas NICD is the nuclear transcription factor activa-tor involving in evolutionarily conserved pathway,mediating short-range intercellular communication andcell-fate determination in development as well as inadulthood. Presenilins mutations affect the productionof Aβ as well as the generation of NICD, indicating thatpresenilins mutations influence both γ- and ε-cleavages.However, recent studies indicate that γ and ε cleavagesare distinct enzymatic events with their own enzymatickinetics and pharmaceutical characterization, and theycan be differentially affected by the FAD-associated PSmutations. Fukumori and colleagues reported that theinhibition of endocytosis of PS1 altered AICD formationwithout changing Aβ42/Aβ40, implying that the effi-ciency of γ and ε cleavage of γ-secretase are differentevent in plasma membrane and endosome, respectively[120]. Parallel study on TMP21 directly pointed out thatTMP21 acted as γ-secretase modulator but affected γcleavage only [121]. The artificial PSΔE10 impaired thenormal Aβ generation but spared the intracellular do-main production in both APP and Notch, supporting thepossibility that γ- and ε-cleavages are dissociated [122].Using in vitro enzyme kinetics assays, De Strooper andhis team demonstrated that PS mutations consistentlyexhibited impaired γ-cleavage activity with altered Aβ42/40 ratio, but the effect on the ICD-producing ε-cleavagewas varied and substrate-specific. For instance, PSM139Vdisplayed enhanced ε-cleavage in N-cadherin but un-changed in APP, Notch and Erb4 [123]. All those studiesindicated that the inefficient processing on ε-cleavageand the impaired Notch-signaling are not essential forAD pathogenesis.Presenilins beyond γ-secretaseRecently, mounting evidence has supported that presenilinscarry out multiple functions beyond the catalytic functionsof γ-secretase. The conditional knock-out of presenilinsin excitatory neurons demonstrated age-dependentneurodegeneration, indicating an essential role ofpresenilins in neurodegeneration independent of amyl-oid cascade [124,125]. However, given the fundamentalfunction of Notch, it is hard to exclude that the pheno-types in conditional PS knock-out mice is due to theimpaired Notch signaling. In the moss Physcomitrellapatens (P. patens), which lacks Notch signaling,presenilin-deficit phenotype could be rescued by wild typepresenilins as well as PS mutants without γ-secretase ac-tivity, indicating other functions of PS beyond γ-secretaseactivity [126]. Moreover, presenilins-knock-out miceexhibited more severe somite phenotype than mice lack-ing canonical Notch-signaling and mice deficient ofNicastrin, Aph-1 or Pen-2, which could still develop anter-ior somite [127]. In summary, all these clues point to theexistence of independent functions of presenilins beyondγ-secretase.FAD-associated presenilins mutations exhibit not onlysignificant heterogeneity on clinical features like age ofonset, neurological and psychiatric symptoms, but alsoon neuropathology including greater NTF formation, al-tered neuritic plaque composition, presence of Pickbody, and neuropathological lesion in basal ganglia andbrainstem [128-130]. It is also reported that presenilinsare involved in Wnt signaling, cell adhesion, calciumhomeostasis, protein degradation and apoptosis, raisingthe possibility that γ-secretase-independent function ofpresenilins might contribute to the presenilins mutations-associated heterogeneity. The subsequent sections of thisreview will focus on these issues (Figure 4).PS1 and β-cateninβ-Catenin in Wnt-signaling and cell-cell adhesionβ-Catenin is a signal transducer protein in Wnt-signaling pathway as well as a cell adhesion molecule[131]. β-Catenin carries out two distinct functionsaccording to its cellular location: the membrane β-cateninforms complex with E-cadherin as cell-cell adhesion mol-ecule; whereas the cytoplasmic β-catenin is involved inWnt-signaling pathway to regulate gene expression. In theabsence of Wnt ligand, β-Catenin undergoes phosphoryl-ation by Glycogen Synthase Kinase-3β (GSK3β) with theassistance of Axin/APC complex, and then the phosphor-ylated β-catenin is constitutively degraded in ubiquitinproteasome pathway. Binding of Wnt to its receptorFrizzled and co-receptor LRP5/6 blocks phosphorylationof β-catenin by GSK3β, precluding the degradation ofβ-catenin. β-catenin is translocated into nuclear to activatetranscriptional factor like T-cell-specific transcriptionalfactor 1 (TCF), to regulate target genes like cyclin D1, c-myc, and metalloproteases. On the other hand, membraneβ-catenin acts as a bridge to link cadherins to α-catenin,and the latter binds to actin network, to stabilize adher-ence junctions as well as the cytoskeleton [131].PS1/β-catenin interaction and ADPS1 negatively regulates β-catenin level via physicallyinteracting with β-catenin through the cytosolic-loopstructure of PS1 [132-136]. This function of PS1 isγ-secretase-independent since the D257A mutant couldrescue the turnover of β-catenin as wild type PS1 does[137]. Though evidence supports the idea that PS1 worksas a scaffold to facilitate β-catenin phosphorylation,the underlying mechanism remains to be elucidated[136-138].It has been reported that the stabilization of β-catenincontributes to the development of skin cancer in PS1-Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 5 of 13http://www.translationalneurodegeneration.com/content/2/1/15deficient mice [139]. However, the precise role of β-cateninin AD pathogenesis is not clear. Most studies on sporadicAD indicated that reduced Wnt/β-catenin signaling mightmake a contribution to AD pathogenesis [140]. However,the studies on FAD were conflicting, some PS mutationswere found to stabilize β-catenin while others destabilizedit [132,136,137,141-143].Presenilins and calcium regulationInteraction of presenilins and calcium channelsPresenilins mutations have been reported to connectwith abnormal intracellular calcium signaling, andpresenilins mutations promote the release of Ca2+ fromoverloaded ER stores through IP3 receptor [144].Presenilins could interact with IP3 receptors to regulateIP3 channel activity. Using patch-clamp techniques,PS1M146L and PS2N141I prolonged IP3 channel openingand increased Ca2+ leak permeability [145]. Studies onprimary neurons from PS1M146V-expressing mice re-vealed that mutant PS1 increased the expression and re-cruitment of ryanodine receptor (RyanR) to regulate theIP3R Ca2+ signaling in primary neurons [146-148]. Apartfrom IP3 receptor and RyanR, prensenilins were alsoreported to interact with sarco-/endoplasmic reticulumCa2+ ATPase (SERCA) to regulate intracellular calciumsignaling [149]. These studies suggested that presenilinsand their mutants regulate intracellular Ca2+ signalingvia interacting with various calcium channel-relatedproteins.Presenilins themselves as Ca2+ leak channelsPresenilins themselves were reported to function aslow-conductance, passive ER Ca2+ leak channels,which is independent of γ-secretase activity [150].Many FAD mutants (e.g. PS1M146V and PS2N141I) dis-rupt or abolish the Ca2+ leak channel activity, leadingto overload of Ca2+ in ER [151]. It has been reportedthat presenilin transmembrane domain 7 and 9 con-tribute to the forming of the ion conductance pore,and transmembrane water-filled catalytic cavity ofpresenilin constitutes the Ca2+ leak channel [152].However, Ca2+ channel function of presenilins hasbeen challenged by another group, showing that FADPS mutants regulate calcium level by regulating IP3RNotchNICDPlaque-Secretase dependent functions-Secretase independent functionsNotch signaling pathwayEmbryonic development and neurogenesis.-Catenin-CateninP PPGSKScafoldding-CateninPP PUb UbUbiquitinationProteasome degradation-CateninWnt signaling pathwayPresenilinsAVs AccumulationAutophagesomeLysosomePresenilins-/-Ca2+ERCa2+ Ca2+IP3RPresenilinsRyanRSERCATargeted genes:Cyclin D1, c-mycand metalloproteases.APPAICD?PresenilinsPen-2 Aph-1 NctNucleusExtracellular -Secretase complexCytoplasmSynaptic activityFigure 4 Presenilin functions. This diagram divides the functions of presenilins into γ-secretase-dependent and γ-secretase-independent onesby the vertical dash line. The γ-secretase activity of presenilins are exemplified by APP processing and Notch processing. Other γ-secretaseindependent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway, regulating calcium homeostasis and its interactionwith synaptic transmission. APP, amyloid β precursor protein; AICD, APP intracellular domain; NICD, Notch intracellular domain; Nct, Nicastrin; IP3,Inositol trisphosphate receptor; SERCA, Sarco/endoplasmic reticulum Ca2+−ATPase; Ryan R, Ryanodine receptor; GSK, Glycogen synthase kinase.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 6 of 13http://www.translationalneurodegeneration.com/content/2/1/15channel gating [145,153]. Further studies on the crystalstructure of presenilin would be helpful to elucidatewhether presenilins themselves act as Ca2+ channels.Dysregulation of autophagy in AD and PS-associatedcalcium abnormalityThe accumulation of autophagic vacuoles (AVs) has beenobserved in dystrophic neurites around the amyloidplaques for decades [154-156]. Autophagy serves as cellularprocessing for dysfunctional cellular organelles and toxicprotein degradation, important for cell survival understress like nutrient deprivation. Autophagy mainly involvestwo steps: generation of autophagosome containing dys-functional cellular organelles and degradation of the con-tents via fusing with lysosome or late endosome [157,158].It has been well established that PS deficiency impairsthe turnover of long-lived proteins like telencephalin(TLN)and α-synuclein [159,160], which results from the lysosomefusion failure and autophagy deficit. In PS1−/− hippocampalneurons, TLN is accumulated in intracellular membraneorganelles containing Apg12p and LC3, the autophagicvacuole markers, in both ultrastructure and immunostain-ing experiments [159,161]. The accumulation of TLNcould be rescued by PS1WT, FAD-associated PS1 mutantsor dominant-negative PS1 mutant (PS1D257A), indicatingthat the PS-associated autophagic vacuoles accumulationwas independent of γ-secretase activity. The accumulationof autophagic vacuoles may be caused either by increasedproduction of autophagic vacuoles, resulting from acceler-ated autophagy activity; or by reduced consumption,resulting from dysfunctional fusion with the lysosome/en-dosome. Given that the formation of TLN-positiveautophagosome triggered by microbeads was normal, theauthors proposed that observed accumulation of TLN-positive autophagic vacuoles was correlated with failedlysosome fusion, which was in accordance with mountingevidence supporting lysosome deficit as the underlyingcause of the autophagy deficit in AD [160,162].Other hypotheses explaining PS1-related autophagicvacuole accumulation involves the lysosome acidificationdeficiency. Lee et al. reported that PS1 acted as chaperoneprotein to facilitate the glycosylation of V-ATPase subunitV0a1, which helped V-ATPase traffic to lysosome andcompleted lysosome acidification [163]. The failed acidifi-cation of lysosome in PS1−/− blastocyst-derived cell line(BD15) repressed the fusion of lysosome with intermediateAVs, resulting in accumulation of AVs. However, laterstudies argued that lysosome acidification appeared to beunimpaired in PS1−/−/PS2−/− stem cells and the glycosyla-tion of V0a1 subunit was unaffected. Nevertheless, Coenet al. demonstrated that the calcium loading of lysosomein PS1−/− or PS1−/−/PS2−/− cells was significantly less thanwild type cells, which could be rescued by PS1 mutantwithout γ-secretase activity, indicating the γ-secretase-independent property. Given that PS1 itself could actas ER Ca2+ leak channels, they proposed that the accu-mulation of autophagic vacuoles often observed in ADcould be interpreted by impaired PS1-related calciumabnormality [164-166].It is well known that PS deficiency is related with AV ab-normality [160,165], however, the relationship betweenautophagy and FAD-associated PS1 mutations is not welldefined. For example, Esselens et al. reported that FAD-associated PS1 mutations rescued PS1 deficiency-relatedTLN-positive autophagy deficit; whereas Lee et al.reported autophagy deficit in PS FAD mutations humanfibroblast. Thus, it needs further investigation to clarifythe contribution of FAD-associated PS1 mutations to au-tophagy deficit of AD.Correlation of Cotton wool plaques (CWP) and abnormalCalcium signalingCWP are large, non-cored and diffuse amyloid plaques,which are composed primarily of Aβ42 without sur-rounding neuritic dystrophy and glial activation inAlzheimer cases [167]. CWP is often associated withspastic paraparesis (SP) [168], both of which werereported in a subset of PS1 mutants like PS1M233T,PS1R278T and PS1ΔE9 [169,170]. The mechanism under-lying these unique clinical and pathological phenotypesis unknown. It is well established that Ca2+ release fromintracellular stores is increased in both sporadic and fa-milial AD [171-173], and thus it is proposed that the dis-turbed Ca2+ regulation in FAD is correlated with CWP[174,175]. Over 20 PS1 mutations have been analyzedand though all PS1 mutations show increased Aβ42/40ratio, their effects on calcium signaling are various. It’svery illuminating to correlate calcium dysfunction withFAD variant phenotypes, but the underlying mechanismneeds further investigation.Presenilins and synaptic transmissionAnother pathological aspect of Alzheimer’s Disease is thefailure of synaptic transmission and further disturbance inthe neural circuit. Many believe that independent ofplaque formation, impairment of synaptic function is whataccounts for AD pathogenesis [176]. It has been reportedthat Aβ plays an important role in maintaining efficientsynaptic transmission and stabilizing the neural circuit[30,177]. Recently presenilins stand out to be a candidateparticipating in the release of neurotransmitter and synap-tic scaling independent of their γ-secretase function. Itwas reported that presenilins are essential for regulatingneurotransmitter release like glutamate [178]. Presynapticknockout of presenilins leads to inhibition of theta burst-induced long-term potentiation. Moreover, the inhibitioneffect is probably mediated by depletion of endoplasmicreticulum Ca2+ storage and blockade of intracellular Ca2+Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 7 of 13http://www.translationalneurodegeneration.com/content/2/1/15release [178]. PS1 was also proposed to regulate homeo-static synaptic scaling [179]. PS1 knockout and PSM146Vneurons fail to scale up synaptic strengths in response totetrodotoxin treatment, which can be rescued by viral ex-pression of wild type PS1. Furthermore, γ-secretase inhibi-tor does not influence the effect of presenilins on synapticscaling, suggesting that this function is independent ofγ-secretase in AD pathogenesis. On the other hand,synaptic activity can in turn modulate the activity ofPS1 such as regulating Aβ40/42 ratio via altering PS1conformation, thereby forming bidirectional inter-action [180]. Using a Cer-PS1-Cit FRET sensor, thegroup discovered that spike bursts trigger PS1 con-formational change through vesicle exocytosis. Moreimportantly, the conformational change of wild typePS1 upregulates Aβ40/42 ratio, which is uniformly de-creased in almost all cases of FAD mutations. Overall,mounting evidence points to a role of presenilins insynaptic transmission. However, the underlying mech-anism is still not clear. The comprehensive interactionbetween presenilins and synaptic activity could result frompresenilin’s functions independent and/or dependent ofγ-secretase activity.Conclusionγ-secretase sequentially processes its substrates at ε- andγ-sites and the enzymatic activities on two cleavages aredistinct. As the catalytic component of the γ-secretasecomplex, FAD-associated presenilins affect γ-secretaseactivity on the γ-site but the effects on ε-cleavage vary.These studies suggest the possibility of development ofγ-secretase modulators sparing the Notch signaling inthe future. It has long been observed that presenilins areinvolved in functions independent of the γ-secretase ac-tivity, like interaction with β-catenin/Wnt signaling, cal-cium regulation and autophagy degradation. However,its contribution to AD pathogenesis is not clear. Furtherstudies are needed to clearly define the function ofpresenilins and its role in AD pathogenesis.AbbreviationsAD: Alzheimer’s disease; PS: Pensenilin; APP: amyloid β precursor proteins;BACE1: Beta-site APP cleaving enzyme 1; Aβ: Amyloid β protein.Competing interestThe authors declared that they have no competing interest.Authors’ contributionsSZ carried out literature search and drafted the manuscript. MZ wrote onesection and critically revised the manuscript. FC drafted one of the figuresand provided comments for the manuscript. WS was the supervisor of theresearch group, provided the guidance and instructions and critically revisedthe manuscript. All authors read and approved the final manuscript.AcknowledgementsThis work was supported by Canadian Institutes of Health Research (CIHR)Operating Grant CCI-117952. W.S. was the holder of the Tier 1 CanadaResearch Chair in Alzheimer's Disease. S. Z. was the recipient of the ChineseScholarship Council award. M. Z. is supported by UBC 4YF Scholarship.Received: 19 May 2013 Accepted: 14 July 2013Published: 17 July 2013References1. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC:Characterization and chromosomal localization of a cDNA encodingbrain amyloid of Alzheimer’s disease. Science 1987, 235:877–880.2. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH,Multhaup G, Beyreuther K, Muller-Hill B: The precursor of Alzheimer’s diseaseamyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325:733–736.3. Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM: Molecular cloning andcharacterization of a cDNA encoding the cerebrovascular and the neuriticplaque amyloid peptides. Proc Natl Acad Sci U S A 1987, 84:4190–4194.4. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC,Myers RH, Feldman RG, Pollen D, Drachman D, et al: The genetic defectcausing familial Alzheimer’s disease maps on chromosome 21. Science 1987,235:885–890.5. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML,Patterson D, Pagan S, Kurnit DM, Neve RL: Amyloid beta protein gene: cDNA,mRNA distribution, and genetic linkage near the Alzheimer locus. Science1987, 235:880–884.6. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L,Haynes A, Irving N, James L, et al: Segregation of a missense mutation in theamyloid precursor protein gene with familial Alzheimer’s disease.Nature 1991, 349:704–706.7. Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E,White JA, Bonnycastle L, Weber JL, Alonso ME, et al: Genetic linkageevidence for a familial Alzheimer’s disease locus on chromosome 14.Science 1992, 258:668–671.8. St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-VanceM, Foncin JF, Montesi M, Bruni A, Sorbi S, et al: Genetic evidence for anovel familial Alzheimer’s disease locus on chromosome 14. Nat Genet1992, 2:330–334.9. Li J, Ma J, Potter H: Identification and expression analysis of a potentialfamilial Alzheimer disease gene on chromosome 1 related to AD3. ProcNatl Acad Sci U S A 1995, 92:12180–12184.10. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H,Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP,Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A,Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA,Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH: Cloningof a gene bearing missense mutations in early-onset familial Alzheimer’sdisease. Nature 1995, 375:754–760.11. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH,Yu CE, Jondro PD, Schmidt SD, Wang K, et al: Candidate gene for thechromosome 1 familial Alzheimer’s disease locus. Science 1995, 269:973–977.12. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL,Bird TD, Schellenberg GD: A familial Alzheimer’s disease locus onchromosome 1. Science 1995, 269:970–973.13. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H,Lin C, Holman K, Tsuda T, et al: Familial Alzheimer’s disease in kindredswith missense mutations in a gene on chromosome 1 related to theAlzheimer’s disease type 3 gene. Nature 1995, 376:775–778.14. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, SmallGW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoproteinE type 4 allele and the risk of Alzheimer’s disease in late onset families.Science 1993, 261:921–923.15. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J,Salvesen GS, Roses AD: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familialAlzheimer disease. Proc Natl Acad Sci U S A 1993, 90:1977–1981.16. Glenner GG, Wong CW: Alzheimer’s disease: initial report of thepurification and characterization of a novel cerebrovascular amyloidprotein. Biochem Biophys Res Commun 1984, 120:885–890.17. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y: Visualizationof A beta 42(43) and A beta 40 in senile plaques with end-specific Abeta monoclonals: evidence that an initially deposited species is A beta42(43). Neuron 1994, 13:45–53.18. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM:Microtubule-associated protein tau. A component of Alzheimer pairedhelical filaments. J Biol Chem 1986, 261:6084–6089.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 8 of 13http://www.translationalneurodegeneration.com/content/2/1/1519. Kosik KS, Joachim CL, Selkoe DJ: Microtubule-associated protein tau (tau)is a major antigenic component of paired helical filaments in Alzheimerdisease. Proc Natl Acad Sci U S A 1986, 83:4044–4048.20. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A: Cloning andsequencing of the cDNA encoding a core protein of the paired helicalfilament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 1988, 85:4051–4055.21. Iqbal K, Grundke-Iqbal I, Smith AJ, George L, Tung YC, Zaidi T: Identificationand localization of a tau peptide to paired helical filaments of Alzheimerdisease. Proc Natl Acad Sci U S A 1989, 86:5646–5650.22. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S,Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, vanBaren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J,Morris JC, Reed LA, Trojanowski J, Basun H, et al: Association of missenseand 5'-splice-site mutations in tau with the inherited dementia FTDP-17.Nature 1998, 393:702–705.23. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ,Ashe KH: Natural oligomers of the amyloid-beta protein specificallydisrupt cognitive function. Nat Neurosci 2005, 8:79–84.24. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, AsheKH: A specific amyloid-beta protein assembly in the brain impairsmemory. Nature 2006, 440:352–357.25. Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N,Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L: Acceleratingamyloid-beta fibrillization reduces oligomer levels and functional deficitsin Alzheimer disease mouse models. J Biol Chem 2007, 282:23818–23828.26. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL:Natural oligomers of the Alzheimer amyloid-beta protein inducereversible synapse loss by modulating an NMDA-type glutamatereceptor-dependent signaling pathway. J Neurosci 2007, 27:2866–2875.27. Selkoe DJ: Soluble oligomers of the amyloid beta-protein impair synapticplasticity and behavior. Behav Brain Res 2008, 192:106–113.28. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, BrettFM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL,Selkoe DJ: Amyloid-beta protein dimers isolated directly from Alzheimer’sbrains impair synaptic plasticity and memory. Nat Med 2008, 14:837–842.29. Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K,Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP,Klein WL, Mori H: A mouse model of amyloid beta oligomers: theircontribution to synaptic alteration, abnormal tau phosphorylation, glialactivation, and neuronal loss in vivo. J Neurosci 2010, 30:4845–4856.30. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease:progress and problems on the road to therapeutics. Science 2002,297:353–356.31. Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D,Ward PJ: Cleavage of amyloid beta peptide during constitutive processingof its precursor. Science 1990, 248:1122–1124.32. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS,Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS,Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2)as beta-secretase. Mol Cell Neurosci 1999, 14:419–427.33. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M,Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J,Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P,Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V:Purification and cloning of amyloid precursor protein beta-secretasefrom human brain. Nature 1999, 402:537–540.34. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB,Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J,Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J,Rogers G, Citron M: Beta-secretase cleavage of Alzheimer’s amyloidprecursor protein by the transmembrane aspartic protease BACE.Science 1999, 286:735–741.35. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR,Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA,Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease withAlzheimer’s disease beta-secretase activity. Nature 1999, 402:533–537.36. Li Y, Zhou W, Tong Y, He G, Song W: Control of APP processing and Abetageneration level by BACE1 enzymatic activity and transcription. FASEBJ 2006, 20:285–292.37. Brown MS, Ye J, Rawson RB, Goldstein JL: Regulated intramembraneproteolysis: a control mechanism conserved from bacteria to humans.Cell 2000, 100:391–398.38. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, AnnaertW, Von Figura K, Van Leuven F: Deficiency of presenilin-1 inhibits thenormal cleavage of amyloid precursor protein. Nature 1998, 391:387–390.39. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ,Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E,Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C,Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P:Nicastrin modulates presenilin-mediated notch/glp-1 signal transductionand betaAPP processing. Nature 2000, 407:48–54.40. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA:Presenilins are required for gamma-secretase cleavage of beta-APP andtransmembrane cleavage of Notch-1. Nat Cell Biol 2000, 2:463–465.41. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M,Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, HimesCS, Hiebsch R, Ruble C, Nye JS, Curtis D: aph-1 and pen-2 are required forNotch pathway signaling, gamma-secretase cleavage of betaAPP, andpresenilin protein accumulation. Dev Cell 2002, 3:85–97.42. Goutte C, Tsunozaki M, Hale VA, Priess JR: APH-1 is a multipass membraneprotein essential for the Notch signaling pathway in Caenorhabditiselegans embryos. Proc Natl Acad Sci U S A 2002, 99:775–779.43. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C:Reconstitution of gamma-secretase activity. Nat Cell Biol 2003, 5:486–488.44. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ:Gamma-secretase is a membrane protein complex comprised ofpresenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 2003,100:6382–6387.45. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y,Thinakaran G, Iwatsubo T: The role of presenilin cofactors in the gamma-secretase complex. Nature 2003, 422:438–441.46. Lee MK, Slunt HH, Martin LJ, Thinakaran G, Kim G, Gandy SE, Seeger M, KooE, Price DL, Sisodia SS: Expression of presenilin 1 and 2 (PS1 and PS2) inhuman and murine tissues. J Neurosci 1996, 16:7513–7525.47. Levitan D, Greenwald I: Facilitation of lin-12-mediated signalling by sel-12, aCaenorhabditis elegans S182 Alzheimer’s disease gene. Nature 1995,377:351–354.48. Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B,Lendahl U, von Heijne G, Naslund J: A nine-transmembrane domaintopology for presenilin 1. J Biol Chem 2005, 280:35352–35360.49. Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W:Presenilin-1 maintains a nine-transmembrane topology throughout thesecretory pathway. J Biol Chem 2006, 281:26569–26577.50. Walter J, Capell A, Grunberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB,Fraser P, Hyslop PS, Selkoe DJ, Haass C: The Alzheimer’s disease-associatedpresenilins are differentially phosphorylated proteins locatedpredominantly within the endoplasmic reticulum. Mol Med 1996, 2:673–691.51. Culvenor JG, Maher F, Evin G, Malchiodi-Albedi F, Cappai R, Underwood JR,Davis JB, Karran EH, Roberts GW, Beyreuther K, Masters CL: Alzheimer’sdisease-associated presenilin 1 in neuronal cells: evidence forlocalization to the endoplasmic reticulum-Golgi intermediatecompartment. J Neurosci Res 1997, 49:719–731.52. Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, WestawayD, George-Hyslop PS, Cordell B, Fraser P, De Strooper B: Presenilin 1controls gamma-secretase processing of amyloid precursor protein inpre-golgi compartments of hippocampal neurons. J Cell Biol 1999,147:277–294.53. Kim SH, Lah JJ, Thinakaran G, Levey A, Sisodia SS: Subcellular localizationof presenilins: association with a unique membrane pool in culturedcells. Neurobiol Dis 2000, 7:99–117.54. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T,Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA,Copeland NG, Price DL, Sisodia SS: Endoproteolysis of presenilin 1 andaccumulation of processed derivatives in vivo. Neuron 1996, 17:181–190.55. Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T,Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P,Teplow DB, Selkoe DJ: Presenilin proteins undergo heterogeneousendoproteolysis between Thr291 and Ala299 and occur as stableN- and C-terminal fragments in normal and Alzheimer brain tissue.Neurobiol Dis 1997, 3:325–337.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 9 of 13http://www.translationalneurodegeneration.com/content/2/1/1556. Shirotani K, Takahashi K, Ozawa K, Kunishita T, Tabira T: Determination of acleavage site of presenilin 2 protein in stably transfected SH-SY5Y humanneuroblastoma cell lines. Biochem Biophys Res Commun 1997, 240:728–731.57. Jacobsen H, Reinhardt D, Brockhaus M, Bur D, Kocyba C, Kurt H, Grim MG,Baumeister R, Loetscher H: The influence of endoproteolytic processing offamilial Alzheimer’s disease presenilin 2 on abeta42 amyloid peptideformation. J Biol Chem 1999, 274:35233–35239.58. Campbell WA, Reed ML, Strahle J, Wolfe MS, Xia W: Presenilinendoproteolysis mediated by an aspartyl protease activitypharmacologically distinct from gamma-secretase. J Neurochem 2003,85:1563–1574.59. Nyabi O, Bentahir M, Horre K, Herreman A, Gottardi-Littell N, VanBroeckhoven C, Merchiers P, Spittaels K, Annaert W, De Strooper B:Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression andNicastrin glycosylation but remain catalytically inactive in the absence ofwild type Presenilin. J Biol Chem 2003, 278:43430–43436.60. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ: Twotransmembrane aspartates in presenilin-1 required for presenilinendoproteolysis and gamma-secretase activity. Nature 1999, 398:513–517.61. Xia W: Relationship between presenilinase and gamma-secretase.Drug News Perspect 2003, 16:69–74.62. Xia W: From presenilinase to gamma-secretase, cleave to capacitate.Curr Alzheimer Res 2008, 5:172–178.63. Ahn K, Shelton CC, Tian Y, Zhang X, Gilchrist ML, Sisodia SS, Li YM:Activation and intrinsic gamma-secretase activity of presenilin 1.Proc Natl Acad Sci U S A 2010, 107:21435–21440.64. Fukumori A, Fluhrer R, Steiner H, Haass C: Three-amino acid spacing ofpresenilin endoproteolysis suggests a general stepwise cleavage ofgamma-secretase-mediated intramembrane proteolysis. J Neurosci 2010,30:7853–7862.65. Knappenberger KS, Tian G, Ye X, Sobotka-Briner C, Ghanekar SV, GreenbergBD, Scott CW: Mechanism of gamma-secretase cleavage activation: isgamma-secretase regulated through autoinhibition involving thepresenilin-1 exon 9 loop? Biochemistry 2004, 43:6208–6218.66. Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R,Haass C: The biological and pathological function of the presenilin-1Deltaexon 9 mutation is independent of its defect to undergoproteolytic processing. J Biol Chem 1999, 274:7615–7618.67. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J,Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P,Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secretedamyloid beta-protein similar to that in the senile plaques of Alzheimer’sdisease is increased in vivo by the presenilin 1 and 2 and APP mutationslinked to familial Alzheimer’s disease. Nat Med 1996, 2:864–870.68. Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B:Total inactivation of gamma-secretase activity in presenilin-deficientembryonic stem cells. Nat Cell Biol 2000, 2:461–462.69. Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G,Xu H: PEN-2 and APH-1 coordinately regulate proteolytic processing ofpresenilin 1. J Biol Chem 2003, 278:7850–7854.70. Zhao G, Liu Z, Ilagan MX, Kopan R: Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in theabsence of nicastrin. J Neurosci 2010, 30:1648–1656.71. Ahn CK, Woo SH, Park JM: Surface solubilization of phenanthrene bysurfactant sorbed on soils with different organic matter contents.J Hazard Mater 2010, 177:799–806.72. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H: Identification ofdistinct gamma-secretase complexes with different APH-1 variants. J BiolChem 2004, 279:41340–41345.73. Shirotani K, Tomioka M, Kremmer E, Haass C, Steiner H: Pathological activityof familial Alzheimer’s disease-associated mutant presenilin can beexecuted by six different gamma-secretase complexes. Neurobiol Dis 2007,27:102–107.74. Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazzella MJ,Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Ebeling C, Jiang Y,Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D:Dissociated phenotypes in presenilin transgenic mice define functionallydistinct gamma-secretases. Proc Natl Acad Sci U S A 2005, 102:8972–8977.75. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H,De Strooper B: Presenilin clinical mutations can affect gamma-secretaseactivity by different mechanisms. J Neurochem 2006, 96:732–742.76. Wolfe MS, Kopan R: Intramembrane proteolysis: theme and variations.Science 2004, 305:1119–1123.77. Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE III,Sudhof T, Yu G: Nicastrin functions as a gamma-secretase-substratereceptor. Cell 2005, 122:435–447.78. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H: Electronmicroscopic structure of purified, active gamma-secretase reveals anaqueous intramembrane chamber and two pores. Proc Natl Acad Sci U SA 2006, 103:6889–6894.79. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, SelkoeDJ: Cryoelectron microscopy structure of purified gamma-secretase at 12A resolution. J Mol Biol 2009, 385:642–652.80. Sato C, Morohashi Y, Tomita T, Iwatsubo T: Structure of the catalytic poreof gamma-secretase probed by the accessibility of substituted cysteines.J Neurosci 2006, 26:12081–12088.81. Tolia A, Chavez-Gutierrez L, De Strooper B: Contribution of presenilintransmembrane domains 6 and 7 to a water-containing cavity in thegamma-secretase complex. J Biol Chem 2006, 281:27633–27642.82. Sato C, Takagi S, Tomita T, Iwatsubo T: The C-terminal PAL motif andtransmembrane domain 9 of presenilin 1 are involved in the formation ofthe catalytic pore of the gamma-secretase. J Neurosci 2008, 28:6264–6271.83. Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T: Participation oftransmembrane domain 1 of presenilin 1 in the catalytic pore structureof the gamma-secretase. J Neurosci 2010, 30:15943–15950.84. Watanabe N, Image I II, Takagi S, Tominaga A, Image Image I, Tomita T,Iwatsubo T: Functional analysis of the transmembrane domains ofpresenilin 1: participation of transmembrane domains 2 and 6 in theformation of initial substrate-binding site of gamma-secretase. J BiolChem 2010, 285:19738–19746.85. Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C: Thepresenilin C-terminus is required for ER-retention, nicastrin-binding andgamma-secretase activity. EMBO J 2004, 23:4738–4748.86. Steiner H, Winkler E, Haass C: Chemical cross-linking provides a model ofthe gamma-secretase complex subunit architecture and evidence forclose proximity of the C-terminal fragment of presenilin with APH-1.J Biol Chem 2008, 283:34677–34686.87. Takeo K, Watanabe N, Tomita T, Iwatsubo T: Contribution of the gamma-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1Protein. J Biol Chem 2012, 287:25834–25843.88. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y: Structure of a presenilin familyintramembrane aspartate protease. Nature 2013, 493:56–61.89. Struhl G, Adachi A: Requirements for presenilin-dependent cleavage ofnotch and other transmembrane proteins. Mol Cell 2000, 6:625–636.90. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA: Molecular pathways toneurodegeneration. Nat Med 2004, 10(Suppl):S2–S9.91. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA: Proteolytic releaseand nuclear translocation of Notch-1 are induced by presenilin-1 andimpaired by pathogenic presenilin-1 mutations. PNAS 1999, 96:6959–6963.92. Ni CY, Murphy MP, Golde TE, Carpenter G: gamma -Secretase cleavageand nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001,294:2179–2181.93. Kim DY, Ingano LA, Kovacs DM: Nectin-1alpha, an immunoglobulin-likereceptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage. J Biol Chem 2002, 277:49976–49981.94. Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK,Edbauer D, Walter J, Steiner H, Haass C: Presenilin-dependentintramembrane proteolysis of CD44 leads to the liberation of itsintracellular domain and the secretion of an Abeta-like peptide. J BiolChem 2002, 277:44754–44759.95. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L,Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK: A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellulardomain and regulates disassembly of adherens junctions. EMBOJ 2002, 21:1948–1956.96. May P, Reddy YK, Herz J: Proteolytic processing of low density lipoproteinreceptor-related protein mediates regulated release of its intracellulardomain. J Biol Chem 2002, 277:18736–18743.97. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK: ACBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003,114:635–645.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 10 of 13http://www.translationalneurodegeneration.com/content/2/1/1598. Haapasalo A, Kovacs DM: The many substrates of presenilin/gamma-secretase. J Alzheimers Dis 2011, 25:3–28.99. Artavanis-Tsakonas S, Matsuno K, Fortini ME: Notch signaling. Science 1995,268:225–232.100. Kopan R, Schroeter EH, Weintraub H, Nye JS: Signal transduction byactivated mNotch: importance of proteolytic processing and itsregulation by the extracellular domain. Proc Natl Acad Sci U S A 1996,93:1683–1688.101. Struhl G, Fitzgerald K, Greenwald I: Intrinsic activity of the Lin-12 andNotch intracellular domains in vivo. Cell 1993, 74:331–345.102. Kidd S, Lieber T, Young MW: Ligand-induced cleavage and regulation ofnuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev 1998,12:3728–3740.103. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S: Skeletal andCNS defects in Presenilin-1-deficient mice. Cell 1997, 89:629–639.104. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME,Chen HY, Price DL, Van der Ploeg LH, Sisodia SS: Presenilin 1 is requiredfor Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997,387:288–292.105. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS,Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R: Apresenilin-1-dependent gamma-secretase-like protease mediates releaseof Notch intracellular domain. Nature 1999, 398:518–522.106. Sestan N, Artavanis-Tsakonas S, Rakic P: Contact-dependent inhibition of corticalneurite growth mediated by notch signaling. Science 1999, 286:741–746.107. Presente A, Andres A, Nye JS: Requirement of Notch in adulthood forneurological function and longevity. Neuroreport 2001, 12:3321–3325.108. Presente A, Shaw S, Nye JS, Andres AJ: Transgene-mediated RNAinterference defines a novel role for notch in chemosensory startlebehavior. Genesis 2002, 34:165–169.109. Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP,Furukawa K: Involvement of Notch signaling in hippocampal synapticplasticity. Proc Natl Acad Sci U S A 2004, 101:9458–9462.110. Salama-Cohen P, Arevalo MA, Grantyn R, Rodriguez-Tebar A: Notch andNGF/p75NTR control dendrite morphology and the balance ofexcitatory/inhibitory synaptic input to hippocampal neurones throughNeurogenin 3. J Neurochem 2006, 97:1269–1278.111. Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL,Beyreuther K, Evin G: A novel epsilon-cleavage within the transmembranedomain of the Alzheimer amyloid precursor protein demonstrateshomology with Notch processing. Biochemistry 2002, 41:2825–2835.112. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T,Kudo T, Takeda M, Haass C: Presenilins mediate a dual intramembranousgamma-secretase cleavage of Notch-1. EMBO J 2002, 21:5408–5416.113. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N,Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y: Longer forms ofamyloid beta protein: implications for the mechanism of intramembranecleavage by gamma-secretase. J Neurosci 2005, 25:436–445.114. Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawashima M, Ihara Y:Blocking the cleavage at midportion between gamma- and epsilon-sitesremarkably suppresses the generation of amyloid beta-protein.FEBS Lett 2005, 579:2907–2912.115. Kakuda N, Funamoto S, Yagishita S, Takami M, Osawa S, Dohmae N, Ihara Y:Equimolar production of amyloid beta-protein and amyloid precursorprotein intracellular domain from beta-carboxyl-terminal fragment bygamma-secretase. J Biol Chem 2006, 281:14776–14786.116. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M,Funamoto S, Ihara Y: gamma-Secretase: successive tripeptide andtetrapeptide release from the transmembrane domain of beta-carboxylterminal fragment. J Neurosci 2009, 29:13042–13052.117. Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC,Ihara Y: Truncated carboxyl-terminal fragments of beta-amyloidprecursor protein are processed to amyloid beta-proteins 40 and 42.Biochemistry 2004, 43:13532–13540.118. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T,Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI,Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS:Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996, 17:1005–1013.119. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA,Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR:Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specificgamma secretase. Hum Mol Genet 2004, 13:159–170.120. Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K,Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A,Haass C, Takeda M: Presenilin-dependent gamma-secretase on plasmamembrane and endosomes is functionally distinct. Biochemistry 2006,45:4907–4914.121. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y,Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X,Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P: TMP21 is a presenilin complex component thatmodulates gamma-secretase but not epsilon-secretase activity. Nature 2006,440:1208–1212.122. Wanngren J, Ottervald J, Parpal S, Portelius E, Stromberg K, Borgegard T,Klintenberg R, Jureus A, Blomqvist J, Blennow K, Zetterberg H, Lundkvist J,Rosqvist S, Karlstrom H: Second generation gamma-secretase modulatorsexhibit different modulation of Notch beta and Abeta production. J BiolChem 2012, 287(39):32640–32650.123. Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M,Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, WiltfangJ, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, DeStrooper B: The mechanism of gamma-Secretase dysfunction in familialAlzheimer disease. EMBO J 2012, 31:2261–2274.124. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, ShankaranarayanaRao BS, Chattarji S, Kelleher RJ III, Kandel ER, Duff K, Kirkwood A, Shen J:Loss of presenilin function causes impairments of memory and synapticplasticity followed by age-dependent neurodegeneration. Neuron 2004,42:23–36.125. Wines-Samuelson M, Schulte EC, Smith MJ, Aoki C, Liu X, Kelleher RJ III,Shen J: Characterization of age-dependent and progressive corticalneuronal degeneration in presenilin conditional mutant mice. PLoSOne 2010, 5:e10195.126. Khandelwal A, Chandu D, Roe CM, Kopan R, Quatrano RS: Moonlightingactivity of presenilin in plants is independent of gamma-secretase andevolutionarily conserved. Proc Natl Acad Sci U S A 2007, 104:13337–13342.127. Huppert SS, Ilagan MX, De Strooper B, Kopan R: Analysis of Notch functionin presomitic mesoderm suggests a gamma-secretase-independent rolefor presenilins in somite differentiation. Dev Cell 2005, 8:677–688.128. Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW,Kumar-Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T,Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, VanBroeckhoven C, Golde T, Hardy J, Haltia M, Revesz T: Variant Alzheimer’sdisease with spastic paraparesis and cotton wool plaques is caused by PS-1mutations that lead to exceptionally high amyloid-beta concentrations.Ann Neurol 2000, 48:806–808.129. Larner AJ, Doran M: Clinical phenotypic heterogeneity of Alzheimer’sdisease associated with mutations of the presenilin-1 gene.J Neurol 2006, 253:139–158.130. Shepherd C, McCann H, Halliday GM: Variations in the neuropathology offamilial Alzheimer’s disease. Acta Neuropathol 2009, 118:37–52.131. Huang H, He X: Wnt/beta-catenin signaling: new (and old) players andnew insights. Curr Opin Cell Biol 2008, 20:119–125.132. Murayama M, Tanaka S, Palacino J, Murayama O, Honda T, Sun X, Yasutake K,Nihonmatsu N, Wolozin B, Takashima A: Direct association of presenilin-1with beta-catenin. FEBS Lett 1998, 433:73–77.133. Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C,Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, DeStrooper B, He X, Yankner BA: Destabilization of beta-catenin bymutations in presenilin-1 potentiates neuronal apoptosis. Nature 1998,395:698–702.134. Cox RT, McEwen DG, Myster DL, Duronio RJ, Loureiro J, Peifer M: A screenfor mutations that suppress the phenotype of Drosophila armadillo, thebeta-catenin homolog. Genetics 2000, 155:1725–1740.135. Noll E, Medina M, Hartley D, Zhou J, Perrimon N, Kosik KS: Presenilin affectsarm/beta-catenin localization and function in Drosophila. Dev Biol 2000,227:450–464.136. Soriano S, Kang DE, Fu M, Pestell R, Chevallier N, Zheng H, Koo EH:Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoidenhancer factor-1 signaling independently of beta-amyloid precursorprotein and notch processing. J Cell Biol 2001, 152:785–794.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 11 of 13http://www.translationalneurodegeneration.com/content/2/1/15137. Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, Leibowitz G,Levine F, Koo EH: Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer’s disease-linked PS1 mutants inthe beta-catenin-signaling pathway. J Neurosci 1999, 19:4229–4237.138. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH:Presenilin couples the paired phosphorylation of beta-cateninindependent of axin: implications for beta-catenin activation intumorigenesis. Cell 2002, 110:751–762.139. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H:Loss of presenilin 1 is associated with enhanced beta-catenin signaling andskin tumorigenesis. Proc Natl Acad Sci U S A 2001, 98:10863–10868.140. De Ferrari GV, Moon RT: The ups and downs of Wnt signaling inprevalent neurological disorders. Oncogene 2006, 25:7545–7553.141. Nishimura M, Yu G, Levesque G, Zhang DM, Ruel L, Chen F, Milman P,Holmes E, Liang Y, Kawarai T, Jo E, Supala A, Rogaeva E, Xu DM, Janus C,Levesque L, Bi Q, Duthie M, Rozmahel R, Mattila K, Lannfelt L, Westaway D,Mount HT, Woodgett J, St George-Hyslop P, et al: Presenilin mutationsassociated with Alzheimer disease cause defective intracellulartrafficking of beta-catenin, a component of the presenilin proteincomplex. Nat Med 1999, 5:164–169.142. Kawamura Y, Kikuchi A, Takada R, Takada S, Sudoh S, Shibamoto S,Yanagisawa K, Komano H: Inhibitory effect of a presenilin 1 mutation onthe Wnt signalling pathway by enhancement of beta-cateninphosphorylation. Eur J Biochem 2001, 268:3036–3041.143. Teo JL, Ma H, Nguyen C, Lam C, Kahn M: Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused bya presenilin-1 mutation. Proc Natl Acad Sci U S A 2005, 102:12171–12176.144. Ito E, Oka K, Etcheberrigaray R, Nelson TJ, McPhie DL, Tofel-Grehl B, Gibson GE,Alkon DL: Internal Ca2+ mobilization is altered in fibroblasts from patientswith Alzheimer disease. Proc Natl Acad Sci U S A 1994, 91:534–538.145. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T,Iwatsubo T, Lee VM, Foskett JK: Mechanism of Ca2+ disruption inAlzheimer’s disease by presenilin regulation of InsP3 receptor channelgating. Neuron 2008, 58:871–883.146. Stutzmann GE, Caccamo A, LaFerla FM, Parker I: Dysregulated IP3 signalingin cortical neurons of knock-in mice expressing an Alzheimer’s-linkedmutation in presenilin1 results in exaggerated Ca2+ signals and alteredmembrane excitability. J Neurosci 2004, 24:508–513.147. Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I: Enhancedryanodine receptor recruitment contributes to Ca2+ disruptions in young,adult, and aged Alzheimer’s disease mice. J Neurosci 2006, 26:5180–5189.148. Chakroborty S, Goussakov I, Miller MB, Stutzmann GE: Deviant ryanodinereceptor-mediated calcium release resets synaptic homeostasis inpresymptomatic 3xTg-AD mice. J Neurosci 2009, 29:9458–9470.149. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM: SERCApump activity is physiologically regulated by presenilin and regulatesamyloid beta production. J Cell Biol 2008, 181:1107–1116.150. Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, DeStrooper B, Yu G, Bezprozvanny I: Presenilins form ER Ca2+ leak channels,a function disrupted by familial Alzheimer’s disease-linked mutations.Cell 2006, 126:981–993.151. Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I: FamilialAlzheimer disease-linked mutations specifically disrupt Ca2+ leakfunction of presenilin 1. J Clin Invest 2007, 117:1230–1239.152. Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I:Mutagenesis mapping of the presenilin 1 calcium leak conductancepore. J Biol Chem 2011, 286:22339–22347.153. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK:Gain-of-function enhancement of IP3 receptor modal gating by familialAlzheimer’s disease-linked presenilin mutants in human cells and mouseneurons. Sci Signal 2010, 3:ra22.154. Suzuki K, Terry RD: Fine structural localization of acid phosphatase insenile plaques in Alzheimer’s presenile dementia. Acta Neuropathol 1967,8:276–284.155. Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C,Nixon RA: Gene expression and cellular content of cathepsin D inAlzheimer’s disease brain: evidence for early up-regulation of theendosomal-lysosomal system. Neuron 1995, 14:671–680.156. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM:Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005, 64:113–122.157. Klionsky DJ, Emr SD: Autophagy as a regulated pathway of cellulardegradation. Science 2000, 290:1717–1721.158. Levine B, Klionsky DJ: Development by self-digestion: molecularmechanisms and biological functions of autophagy. Dev Cell 2004, 6:463–477.159. Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, ZhengH, Saftig P, De Strooper B, Klumperman J, Annaert W: Presenilin 1 mediatesthe turnover of telencephalin in hippocampal neurons via anautophagic degradative pathway. J Cell Biol 2004, 166:1041–1054.160. Wilson CA, Murphy DD, Giasson BI, Zhang B, Trojanowski JQ, Lee VM:Degradative organelles containing mislocalized alpha-and beta-synuclein proliferate in presenilin-1 null neurons. J Cell Biol 2004,165:335–346.161. Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, CraessaertsK, De Strooper B: Interaction with telencephalin and the amyloidprecursor protein predicts a ring structure for presenilins. Neuron 2001,32:579–589.162. Nixon RA, Yang DS: Autophagy failure in Alzheimer’s disease–locating theprimary defect. Neurobiol Dis 2011, 43:38–45.163. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM,Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, CuervoAM, Nixon RA: Lysosomal proteolysis and autophagy require presenilin 1and are disrupted by Alzheimer-related PS1 mutations. Cell 2010,141:1146–1158.164. Neely KM, Green KN, LaFerla FM: Presenilin is necessary for efficientproteolysis through the autophagy-lysosome system in a gamma-secretase-independent manner. J Neurosci 2011, 31:2781–2791.165. Coen K, Flannagan RS, Baron S, Carraro-Lacroix LR, Wang D, Vermeire W,Michiels C, Munck S, Baert V, Sugita S, Wuytack F, Hiesinger PR, Grinstein S,Annaert W: Lysosomal calcium homeostasis defects, not proton pumpdefects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J CellBiol 2012, 198:23–35.166. Zhang X, Garbett K, Veeraraghavalu K, Wilburn B, Gilmore R, Mirnics K,Sisodia SS: A role for presenilins in autophagy revisited: normalacidification of lysosomes in cells lacking PSEN1 and PSEN2. J Neurosci2012, 32:8633–8648.167. Tabira T, Chui DH, Nakayama H, Kuroda S, Shibuya M: Alzheimer’s diseasewith spastic paresis and cotton wool type plaques. J Neurosci Res 2002,70:367–372.168. Karlstrom H, Brooks WS, Kwok JB, Broe GA, Kril JJ, McCann H, Halliday GM,Schofield PR: Variable phenotype of Alzheimer’s disease with spasticparaparesis. J Neurochem 2008, 104:573–583.169. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J,Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B,Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN: Two novel(M233T and R278T) presenilin-1 mutations in early-onset Alzheimer’sdisease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 1997, 8:1537–1542.170. Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M,Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H,Ylikoski R, Poyhonen M, Kucera S, Haltia M: A variant of Alzheimer’s diseasewith spastic paraparesis and unusual plaques due to deletion of exon 9of presenilin 1. Nat Med 1998, 4:452–455.171. Gant JC, Sama MM, Landfield PW, Thibault O: Early and simultaneousemergence of multiple hippocampal biomarkers of aging is mediated byCa2+ −induced Ca2+ release. J Neurosci 2006, 26:3482–3490.172. Foster TC: Calcium homeostasis and modulation of synaptic plasticity inthe aged brain. Aging Cell 2007, 6:319–325.173. Toescu EC, Verkhratsky A: The importance of being subtle: small changesin calcium homeostasis control cognitive decline in normal aging.Aging Cell 2007, 6:267–273.174. Nelson O, Supnet C, Liu H, Bezprozvanny I: Familial Alzheimer’s diseasemutations in presenilins: effects on endoplasmic reticulum calciumhomeostasis and correlation with clinical phenotypes. J Alzheimers Dis 2010,21:781–793.175. Supnet C, Bezprozvanny I: Presenilins as endoplasmic reticulum calcium leakchannels and Alzheimer’s disease pathogenesis. Sci China Life Sci 2011,54:744–751.176. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D,Malenka RC, Nicoll RA, Mucke L: Plaque-independent disruption of neuralcircuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 1999,96:3228–3233.Zhang et al. Translational Neurodegeneration 2013, 2:15 Page 12 of 13http://www.translationalneurodegeneration.com/content/2/1/15177. Palop JJ, Mucke L: Amyloid-beta-induced neuronal dysfunction inAlzheimer’s disease: from synapses toward neural networks.Nat Neurosci 2010, 13:812–818.178. Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I,Sudhof TC, Shen J: Presenilins are essential for regulatingneurotransmitter release. Nature 2009, 460:632–636.179. Pratt KG, Zimmerman EC, Cook DG, Sullivan JM: Presenilin 1 regulateshomeostatic synaptic scaling through Akt signaling. Nat Neurosci 2011,14:1112–1114.180. Dolev I, Fogel H, Milshtein H, Berdichevsky Y, Lipstein N, Brose N, Gazit N,Slutsky I: Spike bursts increase amyloid-beta 40/42 ratio by inducing apresenilin-1 conformational change. Nat Neurosci 2013, 16:587–595.doi:10.1186/2047-9158-2-15Cite this article as: Zhang et al.: Biological function of Presenilin and itsrole in AD pathogenesis. Translational Neurodegeneration 2013 2:15.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitZhang et al. Translational Neurodegeneration 2013, 2:15 Page 13 of 13http://www.translationalneurodegeneration.com/content/2/1/15


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