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γ-Secretase-Regulated Mechanisms Similar to Notch Signaling May Play a Role in Signaling Events, Including APP Signaling, Which Leads to Alzheimer’s Disease

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Abstract

Although γ-secretase was first identified as a protease that cleaves amyloid precursor protein (APP) within the transmembrane domain, thus producing Aβ peptides that are thought to be pathogenic in Alzheimer’s disease (AD), its physiological functions have not been fully elucidated. In the canonical Notch signaling pathway, intramembrane cleavage by γ-secretase serves to release an intracellular domain of Notch that shows activity in the nucleus through binding to transcription factors. Many type 1 transmembrane proteins, including Notch, Delta, and APP, have recently been shown to be substrates for γ-secretase, and their intracellular domains are released from the cell membrane following cleavage by γ-secretase. The common enzyme γ-secretase modulates proteolysis and the turnover of possible signaling molecules, which has led to the attractive hypothesis that mechanisms similar to Notch signaling contribute widely to proteolysis-regulated signaling pathways. APP is also likely to have a signaling mechanism, although the physiological functions of APP have not been elucidated. Indeed, we have shown that the intracellular domain of APP alters gene expression and induces neuron-specific apoptosis. These results suggest that APP signaling responds to the onset of AD. Here, we review the possibility of γ-secretase-regulated signaling, including APP signaling, which leads to AD.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

AICD:

The intracellular domain of APP

bHLH:

Basic helix-loop-helix

C. elegans :

Caenorhabditis elegans

Dll:

Delta-like protein

Dll1IC:

The intracellular domain of Dll1

EGF:

Epidermal growth factor

GO:

Gene ontology

Hes:

Hairy/enhancer of split

JM:

Juxtamembrane

PS:

Presenilin

ICD:

Intracellular domain

NICD:

The intracellular domain of Notch

RA:

All-trans-retinoic acid

RIP:

The regulated intramembrane proteolysis

TM:

Transmembrane

References

  • Abbott A (2008) The plaque plan. Nature 456:161–164

    PubMed  CAS  Google Scholar 

  • Akazawa C, Sasai Y, Nakanishi S, Kageyama R (1992) Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. J Biol Chem 267:21879–21885

    PubMed  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268:225–232

    PubMed  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    PubMed  CAS  Google Scholar 

  • Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG (2002) Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell 110:55–67

    PubMed  CAS  Google Scholar 

  • Bettenhausen B, Hrabe de Angelis M, Simon D, Guenet JL, Gossler A (1995) Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121:2407–2418

    PubMed  CAS  Google Scholar 

  • Bibel M, Richter J, Schrenk K, Tucker KL, Staiger V, Korte M, Goetz M, Barde YA (2004) Differentiation of mouse embryonic stem cells into a defined neuronal lineage. Nat Neurosci 7:1003–1009

    PubMed  CAS  Google Scholar 

  • Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW (2004) Incipient Alzheimer’s disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 101:2173–2178

    PubMed  CAS  Google Scholar 

  • Bolos V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363

    PubMed  CAS  Google Scholar 

  • Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100:391–398

    PubMed  CAS  Google Scholar 

  • Buoso E, Lanni C, Schettini G, Govoni S, Racchi M (2010) beta-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. Pharmacol Res 62:308–317

    PubMed  CAS  Google Scholar 

  • Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 273:27765–27767

    PubMed  CAS  Google Scholar 

  • Cao X, Sudhof TC (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293:115–120

    PubMed  CAS  Google Scholar 

  • Coulson EJ, Paliga K, Beyreuther K, Masters CL (2000) What the evolution of the amyloid protein precursor supergene family tells us about its function. Neurochem Int 36:175–184

    PubMed  CAS  Google Scholar 

  • Cupers P, Orlans I, Craessaerts K, Annaert W, De Strooper B (2001) The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J Neurochem 78:1168–1178

    PubMed  CAS  Google Scholar 

  • Daigle I, Li C (1993) apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. Proc Natl Acad Sci USA 90:12045–12049

    PubMed  CAS  Google Scholar 

  • Dunwoodie SL, Henrique D, Harrison SM, Beddington RS (1997) Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124:3065–3076

    PubMed  CAS  Google Scholar 

  • Edbauer D, Willem M, Lammich S, Steiner H, Haass C (2002) Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). J Biol Chem 277:13389–13393

    PubMed  CAS  Google Scholar 

  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661

    PubMed  CAS  Google Scholar 

  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248:1122–1124

    PubMed  CAS  Google Scholar 

  • Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H (2000) BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA 97:9712–9717

    PubMed  CAS  Google Scholar 

  • Fleming RJ, Scottgale TN, Diederich RJ, Artavanis-Tsakonas S (1990) The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster. Genes Dev 4:2188–2201

    PubMed  CAS  Google Scholar 

  • Gao Y, Pimplikar SW (2001) The gamma-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc Natl Acad Sci USA 98:14979–14984

    PubMed  CAS  Google Scholar 

  • Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW (2009) Alzheimer’s disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci USA 106:18367–18372

    PubMed  CAS  Google Scholar 

  • Giliberto L, d’Abramo C, Acker CM, Davies P, D’Adamio L (2010) Transgenic expression of the amyloid-beta precursor protein-intracellular domain does not induce Alzheimer’s disease-like traits in vivo. PLoS One 5(7):e11609. doi:10.1371/journal.pone.0011609

    PubMed  Google Scholar 

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    PubMed  CAS  Google Scholar 

  • Guenette SY (2002) A role for APP in motility and transcription? Trends Pharmacol Sci 23:203–205 (discussion 205–206)

    PubMed  CAS  Google Scholar 

  • Haass C, Selkoe DJ (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75:1039–1042

    PubMed  CAS  Google Scholar 

  • Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159

    PubMed  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    PubMed  CAS  Google Scholar 

  • Henderson ST, Gao D, Christensen S, Kimble J (1997) Functional domains of LAG-2, a putative signaling ligand for LIN-12 and GLP-1 receptors in Caenorhabditis elegans. Mol Biol Cell 8:1751–1762

    PubMed  CAS  Google Scholar 

  • Hiratochi M, Nagase H, Kuramochi Y, Koh CS, Ohkawara T, Nakayama K (2007) The Delta intracellular domain mediates TGF-beta/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway. Nucleic Acids Res 35:912–922

    PubMed  CAS  Google Scholar 

  • Ho A, Sudhof TC (2004) Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA 101:2548–2553

    PubMed  CAS  Google Scholar 

  • Hung AY, Koo EH, Haass C, Selkoe DJ (1992) Increased expression of beta-amyloid precursor protein during neuronal differentiation is not accompanied by secretory cleavage. Proc Natl Acad Sci USA 89:9439–9443

    PubMed  CAS  Google Scholar 

  • Ikeuchi T, Sisodia SS (2003) The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent “gamma-secretase” cleavage. J Biol Chem 278:7751–7754

    PubMed  CAS  Google Scholar 

  • Iso T, Sartorelli V, Poizat C, Iezzi S, Wu HY, Chung G, Kedes L, Hamamori Y (2001) HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol Cell Biol 21:6080–6089

    PubMed  CAS  Google Scholar 

  • Iwatsubo T (2004) The gamma-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol 14:379–383

    PubMed  CAS  Google Scholar 

  • Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710

    PubMed  CAS  Google Scholar 

  • Justice NJ, Jan YN (2002) Variations on the Notch pathway in neural development. Curr Opin Neurobiol 12:64–70

    PubMed  CAS  Google Scholar 

  • Kageyama R, Ohtsuka T, Kobayashi T (2007) The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134:1243–1251

    PubMed  CAS  Google Scholar 

  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    PubMed  CAS  Google Scholar 

  • Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ (2001) The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem 276:40288–40292

    PubMed  CAS  Google Scholar 

  • Kimberly WT, Zheng JB, Town T, Flavell RA, Selkoe DJ (2005) Physiological regulation of the beta-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation. J Neurosci 25:5533–5543

    PubMed  CAS  Google Scholar 

  • Klein WL, Krafft GA, Finch CE (2001) Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24:219–224

    PubMed  CAS  Google Scholar 

  • Koo EH, Kopan R (2004) Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nat Med 10(Suppl):S26–S33

    PubMed  Google Scholar 

  • Kopan R, Ilagan MX (2004) Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5:499–504

    PubMed  CAS  Google Scholar 

  • Kopczynski CC, Alton AK, Fechtel K, Kooh PJ, Muskavitch MA (1988) Delta, a Drosophila neurogenic gene, is transcriptionally complex and encodes a protein related to blood coagulation factors and epidermal growth factor of vertebrates. Genes Dev 2:1723–1735

    PubMed  CAS  Google Scholar 

  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 96:3922–3927

    PubMed  CAS  Google Scholar 

  • LaVoie MJ, Selkoe DJ (2003) The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 278:34427–34437

    PubMed  CAS  Google Scholar 

  • Leimeister C, Externbrink A, Klamt B, Gessler M (1999) Hey genes: a novel subfamily of hairy- and enhancer of split related genes specifically expressed during mouse embryogenesis. Mech Dev 85:173–177

    PubMed  CAS  Google Scholar 

  • Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377:351–354

    PubMed  CAS  Google Scholar 

  • Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977

    PubMed  CAS  Google Scholar 

  • Lewis J (1998) Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 9:583–589

    PubMed  CAS  Google Scholar 

  • Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA (2005) Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J 24:2944–2955

    PubMed  CAS  Google Scholar 

  • Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA, McKeel D, Morris JC, Hulette CM, Schmechel D, Reiman EM, Rogers J, Stephan DA (2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genomics 33:240–256

    PubMed  CAS  Google Scholar 

  • Lindsell CE, Shawber CJ, Boulter J, Weinmaster G (1995) Jagged: a mammalian ligand that activates Notch1. Cell 80:909–917

    PubMed  CAS  Google Scholar 

  • Lorenzo A, Yuan M, Zhang Z, Paganetti PA, Sturchler-Pierrat C, Staufenbiel M, Mautino J, Vigo FS, Sommer B, Yankner BA (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat Neurosci 3:460–464

    PubMed  CAS  Google Scholar 

  • Lott IT, Head E (2005) Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiol Aging 26:383–389

    PubMed  CAS  Google Scholar 

  • Luo LQ, Martin-Morris LE, White K (1990) Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursor. J Neurosci 10:3849–3861

    PubMed  CAS  Google Scholar 

  • McCarthy JV, Twomey C, Wujek P (2009) Presenilin-dependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 66:1534–1555

    PubMed  CAS  Google Scholar 

  • McGowan E, Pickford F, Dickson D (2003) Alzheimer animal models: models of Abeta deposition in transgenic mice. In: Dickson D (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 74–79

    Google Scholar 

  • Muller T, Meyer HE, Egensperger R, Marcus K (2008) The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer’s disease. Prog Neurobiol 85:393–406

    PubMed  Google Scholar 

  • Nagase H, Koh CS, Nakayama K (2010) gamma-Secretase-regulated signaling pathways, such as Notch signaling, mediate the differentiation of hematopoietic stem cells, development of the immune system, and peripheral immune responses. Curr Stem Cell Res Ther [Epub ahead of print]

  • Nakayama K, Nagase K, Tokutake Y, Koh CS, Hiratochi M, Ohkawara T, Nakayama N (2004) Multiple POU-binding motifs, recognized by tissue-specific nuclear factors, are important for Dll1 gene expression in neural stem cells. Biochem Biophys Res Commun 325:991–996

    PubMed  CAS  Google Scholar 

  • Nakayama K, Nagase H, Hiratochi M, Koh CS, Ohkawara T (2008a) Similar mechanisms regulated by gamma-secretase are involved in both directions of the bi-directional Notch-Delta signaling pathway as well as play a potential role in signaling events involving type 1 transmembrane proteins. Curr Stem Cell Res Ther 3:288–302

    PubMed  CAS  Google Scholar 

  • Nakayama K, Ohkawara T, Hiratochi M, Koh CS, Nagase H (2008b) The intracellular domain of amyloid precursor protein induces neuron-specific apoptosis. Neurosci Lett 444:127–131

    PubMed  CAS  Google Scholar 

  • Ni CY, Murphy MP, Golde TE, Carpenter G (2001) gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294:2179–2181

    PubMed  CAS  Google Scholar 

  • Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989

    PubMed  CAS  Google Scholar 

  • Ohkawara T, Nagase H, Koh CS, Nakayama K (2011) The amyloid precursor protein intracellular domain alters gene expression and induces neuron-specific apoptosis. Gene 475(1):1–9

    PubMed  CAS  Google Scholar 

  • Park JH, Gimbel DA, GrandPre T, Lee JK, Kim JE, Li W, Lee DH, Strittmatter SM (2006) Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci 26:1386–1395

    PubMed  CAS  Google Scholar 

  • Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (1991) Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 67:687–699

    PubMed  CAS  Google Scholar 

  • Roehl H, Bosenberg M, Blelloch R, Kimble J (1996) Roles of the RAM and ANK domains in signaling by the C. elegans GLP-1 receptor. EMBO J 15:7002–7012

    PubMed  CAS  Google Scholar 

  • Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T et al (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376:775–778

    PubMed  CAS  Google Scholar 

  • Rohn JL, Lauring AS, Linenberger ML, Overbaugh J (1996) Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J Virol 70:8071–8080

    PubMed  CAS  Google Scholar 

  • Rosen DR, Martin-Morris L, Luo LQ, White K (1989) A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. Proc Natl Acad Sci U S A 86:2478–2482

    PubMed  CAS  Google Scholar 

  • Ryan KA, Pimplikar SW (2005) Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol 171:327–335

    PubMed  CAS  Google Scholar 

  • Sarkar NH, Haga S, Lehner AF, Zhao W, Imai S, Moriwaki K (1994) Insertional mutation of int protooncogenes in the mammary tumors of a new strain of mice derived from the wild in China: normal- and tumor-tissue-specific expression of int-3 transcripts. Virology 203:52–62

    PubMed  CAS  Google Scholar 

  • Schnabel J (2009) Alzheimer’s theory makes a splash. Nature 459:310

    PubMed  CAS  Google Scholar 

  • Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382–386

    PubMed  CAS  Google Scholar 

  • Schulz JG, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G (2003) Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J Biol Chem 278:48651–48657

    PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    PubMed  CAS  Google Scholar 

  • Selkoe D, Kopan R (2003) Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565–597

    PubMed  CAS  Google Scholar 

  • Selkoe DJ, Wolfe MS (2007) Presenilin: running with scissors in the membrane. Cell 131:215–221

    PubMed  CAS  Google Scholar 

  • Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE 3rd, Sudhof T, Yu G (2005) Nicastrin functions as a gamma-secretase-substrate receptor. Cell 122:435–447

    PubMed  CAS  Google Scholar 

  • Shawber C, Boulter J, Lindsell CE, Weinmaster G (1996) Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol 180:370–376

    PubMed  CAS  Google Scholar 

  • 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 (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760

    PubMed  CAS  Google Scholar 

  • Shutter JR, Scully S, Fan W, Richards WG, Kitajewski J, Deblandre GA, Kintner CR, Stark KL (2000) Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 14:1313–1318

    PubMed  CAS  Google Scholar 

  • Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL (1993) Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13:3136–3142

    PubMed  CAS  Google Scholar 

  • Six E, Ndiaye D, Laabi Y, Brou C, Gupta-Rossi N, Israel A, Logeat F (2003) The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc Natl Acad Sci U S A 100:7638–7643

    PubMed  CAS  Google Scholar 

  • Slomnicki LP, Lesniak W (2008) A putative role of the Amyloid Precursor Protein Intracellular Domain (AICD) in transcription. Acta Neurobiol Exp (Wars) 68:219–228

    Google Scholar 

  • Soba P, Eggert S, Wagner K, Zentgraf H, Siehl K, Kreger S, Lower A, Langer A, Merdes G, Paro R, Masters CL, Muller U, Kins S, Beyreuther K (2005) Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J 24:3624–3634

    PubMed  CAS  Google Scholar 

  • Struhl G, Adachi A (2000) Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell 6:625–636

    PubMed  CAS  Google Scholar 

  • Tax FE, Yeargers JJ, Thomas JH (1994) Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila. Nature 368:150–154

    PubMed  CAS  Google Scholar 

  • Terry RD, Katzman R, Bick KL, Sisodia SS (1999) Alzheimer’s disease. Lippincott, Williams & Wilkins, Philadelphia

    Google Scholar 

  • 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 (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    PubMed  CAS  Google Scholar 

  • Vazquez MC, Vargas LM, Inestrosa NC, Alvarez AR (2009) c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis. J Cell Physiol 220:136–143

    PubMed  CAS  Google Scholar 

  • Vogt DL, Thomas D, Galvan V, Bredesen DE, Lamb BT, Pimplikar SW (2009) Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.09.002

  • Wallberg AE, Pedersen K, Lendahl U, Roeder RG (2002) p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Mol Cell Biol 22:7812–7819

    PubMed  CAS  Google Scholar 

  • Wang Y, Ha Y (2004) The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 15:343–353

    PubMed  CAS  Google Scholar 

  • Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43:567–581

    PubMed  CAS  Google Scholar 

  • Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD (2000) MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 26:484–489

    PubMed  CAS  Google Scholar 

  • Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta-protein precursor gene. Gene 87:257–263

    PubMed  CAS  Google Scholar 

  • 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 (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407:48–54

    PubMed  CAS  Google Scholar 

  • Zheng H, Koo EH (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1:5

    PubMed  Google Scholar 

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Author notes

  1. Takeshi Ohkawara

    Present address: Department of Developmental and Regenerative Medicine, Graduate School of Medicine, Mie University, Tsu, Mie, 514-8507, Japan

Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan

    Kohzo Nakayama & Takeshi Ohkawara

  2. Department of Immunology and Infectious Diseases, School of Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan

    Hisashi Nagase

  3. Department of Biomedical Sciences, School of Health Sciences, Shinshu University, Matsumoto, Nagano, 390-8621, Japan

    Chang-Sung Koh

Authors
  1. Kohzo Nakayama
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  2. Hisashi Nagase
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  3. Chang-Sung Koh
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  4. Takeshi Ohkawara
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Correspondence to Kohzo Nakayama.

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Nakayama, K., Nagase, H., Koh, CS. et al. γ-Secretase-Regulated Mechanisms Similar to Notch Signaling May Play a Role in Signaling Events, Including APP Signaling, Which Leads to Alzheimer’s Disease. Cell Mol Neurobiol 31, 887–900 (2011). https://doi.org/10.1007/s10571-011-9688-z

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  • DOI: https://doi.org/10.1007/s10571-011-9688-z

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