Experimental Brain Research

, Volume 217, Issue 3–4, pp 397–411 | Cite as

Caenorhabditis elegans as a model organism to study APP function

  • Collin Y. Ewald
  • Chris LiEmail author


The brains of Alzheimer’s disease patients show an increased number of senile plaques compared with normal patients. The major component of the plaques is the β-amyloid peptide, a cleavage product of the amyloid precursor protein (APP). Although the processing of APP has been well-described, the physiological functions of APP and its cleavage products remain unclear. This article reviews the multifunctional roles of an APP orthologue, the C. elegans APL-1. Understanding the function of APL-1 may provide insights into the functions and signaling pathways of human APP. In addition, the physiological effects of introducing human β-amyloid peptide into C. elegans are also reviewed. The C. elegans system provides a powerful genetic model to identify genes regulating the molecular mechanisms underlying intracellular β-amyloid peptide accumulation.


Model system C. elegans apl-1 Alzheimer’s disease Beta amyloid 



We wish to thank Alicia Melendez for her kind gift of the C. elegans strain carrying [RFP::BEC-1], Chris Link, Andrea Silva, and Greg O’Connor for permission to cite unpublished observations and members of our laboratory for many helpful discussions. This work was supported by grants from the Alzheimer’s Association, National Science Foundation, and National Institutes of Health.


  1. Ahringer J (1997) Turn to the worm! Curr Opin Genet Dev 7(3):410–415. doi: S0959-437X(97)80157-8 PubMedGoogle Scholar
  2. Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ (2011) Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472(7342):226–229. doi: 10.1038/nature09873 PubMedGoogle Scholar
  3. Allinquant B, Hantraye P, Mailleux P, Moya K, Bouillot C, Prochiantz A (1995) Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. J Cell Biol 128(5):919–927PubMedGoogle Scholar
  4. An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17(15):1882–1893. doi: 10.1101/gad.11078031107803 PubMedGoogle Scholar
  5. Arimoto M, Koushika SP, Choudhary BC, Li C, Matsumoto K, Hisamoto N (2011) The Caenorhabditis elegans JIP3 protein UNC-16 functions as an adaptor to link kinesin-1 with cytoplasmic dynein. J Neurosci 31(6):2216–2224. doi: 10.1523/JNEUROSCI.2653-10.2011 PubMedGoogle Scholar
  6. Askanas V, Engel WK (2006) Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition. Neurology 66(2 Suppl 1):S39–S48. doi: 10.1212/01.wnl.0000192128.13875.1e PubMedGoogle Scholar
  7. Banwell BL, Engel AG (2000) AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 54(5):1033–1041PubMedGoogle Scholar
  8. Bargmann CI, Horvitz HR (1991) Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7(5):729–742PubMedGoogle Scholar
  9. Barsyte D, Lovejoy DA, Lithgow GJ (2001) Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. Faseb J 15(3):627–634. doi: 10.1096/fj.99-0966com15/3/627 PubMedGoogle Scholar
  10. Bird TD (2010) Early-onset Familial Alzheimer Disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K (eds) GeneReviews. University of Washington, Seattle.
  11. Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299(5606):572–574PubMedGoogle Scholar
  12. Borg JP, Ooi J, Levy E, Margolis B (1996) The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cell Biol 16(11):6229–6241PubMedGoogle Scholar
  13. Botelho MG, Wang X, Arndt-Jovin DJ, Becker D, Jovin TM (2010) Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein. J Invest Dermatol 130(5):1400–1410. doi: 10.1038/jid.2009.296 PubMedGoogle Scholar
  14. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77(1):71–94PubMedGoogle Scholar
  15. Cabrejo L, Guyant-Marechal L, Laquerriere A, Vercelletto M, De la Fourniere F, Thomas-Anterion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D (2006) Phenotype associated with APP duplication in five families. Brain 129(Pt 11):2966–2976PubMedGoogle Scholar
  16. Caille I, Allinquant B, Dupont E, Bouillot C, Langer A, Muller U, Prochiantz A (2004) Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development 131(9):2173–2181. doi: 10.1242/dev.01103dev.01103 PubMedGoogle Scholar
  17. Carmine-Simmen K, Proctor T, Tschape J, Poeck B, Triphan T, Strauss R, Kretzschmar D (2009) Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function. Neurobiol Dis 33(2):274–281. doi: 10.1016/j.nbd.2008.10.014 PubMedGoogle Scholar
  18. Chalfie M, Sulston JE, White JG, Southgate E, Thomson JN, Brenner S (1985) The neural circuit for touch sensitivity in Caenorhabditis elegans. J Neurosci 5(4):956–964PubMedGoogle Scholar
  19. Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC (1994) Green fluorescent protein as a marker for gene expression. Science 263(5148):802–805PubMedGoogle Scholar
  20. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J et al (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353(6347):844–846PubMedGoogle Scholar
  21. Chen F, Gu Y, Hasegawa H, Ruan X, Arawaka S, Fraser P, Westaway D, Mount H, St George-Hyslop P (2002) Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch. J Biol Chem 277(39):36521–36526. doi: 10.1074/jbc.M205093200M205093200 PubMedGoogle Scholar
  22. Chui DH, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 5(5):560–564. doi: 10.1038/8438 PubMedGoogle Scholar
  23. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313(5793):1604–1610PubMedGoogle Scholar
  24. Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A (2009) Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139(6):1157–1169. doi: 10.1016/j.cell.2009.11.014 PubMedGoogle Scholar
  25. Cohen E, Du D, Joyce D, Kapernick EA, Volovik Y, Kelly JW, Dillin A (2010) Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection. Aging Cell 9(2):126–134. doi: 10.1111/j.1474-9726.2009.00541.x PubMedGoogle Scholar
  26. Culetto E, Sattelle DB (2000) A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum Mol Genet 9(6):869–877. doi: ddd102 PubMedGoogle Scholar
  27. 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(24):12045–12049PubMedGoogle Scholar
  28. Dosanjh LE, Brown MK, Rao G, Link CD, Luo Y (2010) Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-beta. J Alzheimers Dis 19(2):681–690. doi: 10.3233/JAD-2010-1267 PubMedGoogle Scholar
  29. Dostal V, Roberts CM, Link CD (2010) Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of beta-amyloid peptide toxicity. Genetics 186(3):857–866. doi: 10.1534/genetics.110.120436 PubMedGoogle Scholar
  30. Drake J, Link CD, Butterfield DA (2003) Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24(3):415–420PubMedGoogle Scholar
  31. Duerr JS, Han HP, Fields SD, Rand JB (2008) Identification of major classes of cholinergic neurons in the nematode Caenorhabditis elegans. J Comp Neurol 506(3):398–408. doi: 10.1002/cne.21551 PubMedGoogle Scholar
  32. Ewald CY, Li C (2010) Understanding the molecular basis of Alzheimer’s disease using a Caenorhabditis elegans model system. Brain Struct Funct 214(2–3):263–283. doi: 10.1007/s00429-009-0235-3 PubMedGoogle Scholar
  33. Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106(8):2700–2705. doi: 10.1073/pnas.0809594106 PubMedGoogle Scholar
  34. Florez-McClure ML, Hohsfield LA, Fonte G, Bealor MT, Link CD (2007) Decreased insulin-receptor signaling promotes the autophagic degradation of beta-amyloid peptide in C. elegans. Autophagy 3(6):569–580PubMedGoogle Scholar
  35. Fonte V, Kapulkin V, Taft A, Fluet A, Friedman D, Link CD (2002) Interaction of intracellular beta amyloid peptide with chaperone proteins. Proc Natl Acad Sci USA 99(14):9439–9444PubMedGoogle Scholar
  36. Fonte V, Kipp DR, Yerg J III, Merin D, Forrestal M, Wagner E, Roberts CM, Link CD (2008) Suppression of in vivo beta-amyloid peptide toxicity by overexpression of the HSP-16.2 small chaperone protein. J Biol Chem 283(2):784–791PubMedGoogle Scholar
  37. 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, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3(1):85–97PubMedGoogle Scholar
  38. Freude S, Hettich MM, Schumann C, Stohr O, Koch L, Kohler C, Udelhoven M, Leeser U, Muller M, Kubota N, Kadowaki T, Krone W, Schroder H, Bruning JC, Schubert M (2009) Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer’s disease. Faseb J 23(10):3315–3324. doi: 10.1096/fj.09-132043 PubMedGoogle Scholar
  39. Freude KK, Penjwini M, Davis JL, LaFerla FM, Blurton-Jones M (2011) Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J Biol Chem 286(27):24264–24274. doi: 10.1074/jbc.M111.227421 PubMedGoogle Scholar
  40. Glenner GG, Wong CW (1984) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135PubMedGoogle Scholar
  41. 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(6311):704–706PubMedGoogle Scholar
  42. Goodman MB, Hall DH, Avery L, Lockery SR (1998) Active currents regulate sensitivity and dynamic range in C. elegans neurons. Neuron 20(4):763–772. doi: S0896-6273(00)81014-4 PubMedGoogle Scholar
  43. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156(1):15–20PubMedGoogle Scholar
  44. Goutte C, Hepler W, Mickey KM, Priess JR (2000) aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127(11):2481–2492PubMedGoogle Scholar
  45. Haass C, Selkoe DJ (1993) Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75(6):1039–1042PubMedGoogle Scholar
  46. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357(6378):500–503. doi: 10.1038/357500a0 PubMedGoogle Scholar
  47. Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ (1993) beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 268(5):3021–3024PubMedGoogle Scholar
  48. Hada K, Asahina M, Hasegawa H, Kanaho Y, Slack FJ, Niwa R (2010) The nuclear receptor gene nhr-25 plays multiple roles in the Caenorhabditis elegans heterochronic gene network to control the larva-to-adult transition. Dev Biol 344(2):1100–1109. doi: 10.1016/j.ydbio.2010.05.508 PubMedGoogle Scholar
  49. Hassan WM, Merin DA, Fonte V, Link CD (2009) AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer’s disease model. Hum Mol Genet 18(15):2739–2747. doi: 10.1093/hmg/ddp209 PubMedGoogle Scholar
  50. Hayes GD, Frand AR, Ruvkun G (2006) The mir-84 and let-7 paralogous microRNA genes of Caenorhabditis elegans direct the cessation of molting via the conserved nuclear hormone receptors NHR-23 and NHR-25. Development 133(23):4631–4641. doi: 10.1242/dev.02655 PubMedGoogle Scholar
  51. Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rulicke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Muller U (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20(21):7951–7963PubMedGoogle Scholar
  52. Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Muller U (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23(20):4106–4115PubMedGoogle Scholar
  53. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421(6919):182–187PubMedGoogle Scholar
  54. Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J 13(11):1385–1393PubMedGoogle Scholar
  55. Hoopes JT, Liu X, Xu X, Demeler B, Folta-Stogniew E, Li C, Ha Y (2010) Structural characterization of the E2 domain of APL-1, a Caenorhabditis elegans homolog of human amyloid precursor protein, and its heparin binding site. J Biol Chem 285(3):2165–2173. doi: 10.1074/jbc.M109.018432 PubMedGoogle Scholar
  56. Hornsten A (2001) APL-1, a Caenorhabditis elegans protein related to the human amyloid precursor protein, is essential for viability. Dissertation, Boston University, BostonGoogle Scholar
  57. Hornsten A, Lieberthal J, Fadia S, Malins R, Ha L, Xu X, Daigle I, Markowitz M, O’Connor G, Plasterk R, Li C (2007) APL-1, a Caenorhabditis elegans protein related to the human beta-amyloid precursor protein, is essential for viability. Proc Natl Acad Sci USA 104(6):1971–1976PubMedGoogle Scholar
  58. Horvitz HR, Chalfie M, Trent C, Sulston JE, Evans PD (1982) Serotonin and octopamine in the nematode Caenorhabditis elegans. Science 216(4549):1012–1014PubMedGoogle Scholar
  59. Hosono R, Sassa T, Kuno S (1987) Mutations affecting acetylcholine levels in the nematode Caenorhabditis elegans. J Neurochem 49(6):1820–1823PubMedGoogle Scholar
  60. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D (1995) Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15(5):1203–1218PubMedGoogle Scholar
  61. Ikin AF, Annaert WG, Takei K, De Camilli P, Jahn R, Greengard P, Buxbaum JD (1996) Alzheimer amyloid protein precursor is localized in nerve terminal preparations to Rab5-containing vesicular organelles distinct from those implicated in the synaptic vesicle pathway. J Biol Chem 271(50):31783–31786PubMedGoogle Scholar
  62. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 103(13):5161–5166PubMedGoogle Scholar
  63. Johnson CD, Duckett JG, Culotti JG, Herman RK, Meneely PM, Russell RL (1981) An acetylcholinesterase-deficient mutant of the nematode Caenorhabditis elegans. Genetics 97(2):261–279PubMedGoogle Scholar
  64. Kaether C, Skehel P, Dotti CG (2000) Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons. Mol Biol Cell 11(4):1213–1224PubMedGoogle Scholar
  65. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28(2):449–459. doi: S0896-6273(00)00124-0 PubMedGoogle Scholar
  66. 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(6106):733–736PubMedGoogle Scholar
  67. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366(6454):461–464PubMedGoogle Scholar
  68. Kerr R, Lev-Ram V, Baird G, Vincent P, Tsien RY, Schafer WR (2000) Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron 26(3):583–594. doi: S0896-6273(00)81196-4 PubMedGoogle Scholar
  69. Kettern N, Dreiseidler M, Tawo R, Hohfeld J (2010) Chaperone-assisted degradation: multiple paths to destruction. Biol Chem 391(5):481–489. doi: 10.1515/BC.2010.058 PubMedGoogle Scholar
  70. Kidd M (1964) Alzheimer’s disease—an electron microscopical study. Brain 87:307–320PubMedGoogle Scholar
  71. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA 100(11):6382–6387. doi: 10.1073/pnas.10373921001037392100 PubMedGoogle Scholar
  72. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87(4):1561–1565PubMedGoogle Scholar
  73. Koo EH, Squazzo SL, Selkoe DJ, Koo CH (1996) Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody. J Cell Sci 109(5):991–998PubMedGoogle Scholar
  74. Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci USA 106(29):12031–12036. doi: 10.1073/pnas.0813248106 PubMedGoogle Scholar
  75. Kounnas MZ, Moir RD, Rebeck GW, Bush AI, Argraves WS, Tanzi RE, Hyman BT, Strickland DK (1995) LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82(2):331–340. doi: 0092-8674(95)90320-8 PubMedGoogle Scholar
  76. Kramer JM (2005) Basement membranes. WormBook 1–15. doi: 10.1895/wormbook.1.16.1
  77. Krigman MR, Feldman RG, Bensch K (1965) Alzheimer’s presenile dementia. A histochemical and electron microscopic study. Lab Invest 14:381–396PubMedGoogle Scholar
  78. Kuester M, Kemmerzehl S, Dahms SO, Roeser D, Than ME (2011) The crystal structure of death receptor 6 (DR6): a potential receptor of the amyloid precursor protein (APP). J Mol Biol 409(2):189–201. doi: 10.1016/j.jmb.2011.03.048 PubMedGoogle Scholar
  79. Kuo YM, Beach TG, Sue LI, Scott S, Layne KJ, Kokjohn TA, Kalback WM, Luehrs DC, Vishnivetskaya TA, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Weller RO, Roher AE (2001) The evolution of Abeta peptide burden in the APP23 transgenic mice: implications for Abeta deposition in Alzheimer disease. Mol Med 7(9):609–618PubMedGoogle Scholar
  80. LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC, Jay G (1995) The Alzheimer’s Abeta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet 9(1):21–30PubMedGoogle Scholar
  81. LaFerla FM, Troncoso JC, Strickland DK, Kawas CH, Jay G (1997) Neuronal cell death in Alzheimer’s disease correlates with apoE uptake and intracellular Abeta stabilization. J Clin Invest 100(2):310–320. doi: 10.1172/JCI119536 PubMedGoogle Scholar
  82. Lee RY, Sawin ER, Chalfie M, Horvitz HR, Avery L (1999) EAT-4, a homolog of a mammalian sodium-dependent inorganic phosphate cotransporter, is necessary for glutamatergic neurotransmission in Caenorhabditis elegans. J Neurosci 19(1):159–167PubMedGoogle Scholar
  83. Lenkkeri U, Kestila M, Lamerdin J, McCready P, Adamson A, Olsen A, Tryggvason K (1998) Structure of the human amyloid-precursor-like protein gene APLP1 at 19q13.1. Hum Genet 102(2):192–196PubMedGoogle Scholar
  84. Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377(6547):351–354PubMedGoogle Scholar
  85. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 93(25):14940–14944PubMedGoogle Scholar
  86. 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(5226):973–977PubMedGoogle Scholar
  87. Li X, Greenwald I (1997) HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling. Proc Natl Acad Sci USA 94(22):12204–12209PubMedGoogle Scholar
  88. Li C, Kim K (2008) Neuropeptides in C. elegans. In: The C. elegans Research Community, WormBook. doi: 10.1895/wormbook.1.142.1.
  89. Li QX, Maynard C, Cappai R, McLean CA, Cherny RA, Lynch T, Culvenor JG, Trevaskis J, Tanner JE, Bailey KA, Czech C, Bush AI, Beyreuther K, Masters CL (1999) Intracellular accumulation of detergent-soluble amyloidogenic Abeta fragment of Alzheimer’s disease precursor protein in the hippocampus of aged transgenic mice. J Neurochem 72(6):2479–2487PubMedGoogle Scholar
  90. Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer RE, Sudhof TC, Zheng H (2010a) Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. Proc Natl Acad Sci USA 107(40):17362–17367. doi: 10.1073/pnas.1012568107 PubMedGoogle Scholar
  91. Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Sudhof TC, Wang R, Zheng H (2010b) Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis. J Biol Chem 285(40):30598–30605. doi: 10.1074/jbc.M110.137729 PubMedGoogle Scholar
  92. Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278(5341):1319–1322PubMedGoogle Scholar
  93. Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92(20):9368–9372PubMedGoogle Scholar
  94. Link CD (2001) Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech Ageing Dev 122(14):1639–1649PubMedGoogle Scholar
  95. Link CD (2005) Invertebrate models of Alzheimer’s disease. Genes Brain Behav 4(3):147–156. doi: 10.1111/j.1601-183X.2004.00105.x PubMedGoogle Scholar
  96. Link CD (2006) C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer’s disease. Exp Gerontol 41(10):1007–1013PubMedGoogle Scholar
  97. Link CD, Johnson CJ, Fonte V, Paupard M, Hall DH, Styren S, Mathis CA, Klunk WE (2001) Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34. Neurobiol Aging 22(2):217–226PubMedGoogle Scholar
  98. Link CD, Taft A, Kapulkin V, Duke K, Kim S, Fei Q, Wood DE, Sahagan BG (2003) Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer’s disease model. Neurobiol Aging 24(3):397–413PubMedGoogle Scholar
  99. Lockery SR, Goodman MB (2009) The quest for action potentials in C. elegans neurons hits a plateau. Nat Neurosci 12(4):377–378. doi: 10.1038/nn0409-377 PubMedGoogle Scholar
  100. Luo L, Tully T, White K (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9(4):595–605PubMedGoogle Scholar
  101. Luse SA, Smith KR Jr (1964) The ultrastructure of senile plaques. Am J Pathol 44(4):553–563PubMedGoogle Scholar
  102. Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89(2–3):169–179PubMedGoogle Scholar
  103. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82(12):4245–4249PubMedGoogle Scholar
  104. McColl G, Roberts BR, Gunn AP, Perez KA, Tew DJ, Masters CL, Barnham KJ, Cherny RA, Bush AI (2009) The Caernorhabditis elegans Abeta1-42 model of Alzheimer’s disease predominantly expresses Abeta3-42. J Biol Chem. doi: 10.1074/jbc.C109.028514
  105. McElwee J, Bubb K, Thomas JH (2003) Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2(2):111–121PubMedGoogle Scholar
  106. McIntire SL, Jorgensen E, Kaplan J, Horvitz HR (1993) The GABAergic nervous system of Caenorhabditis elegans. Nature 364(6435):337–341. doi: 10.1038/364337a0 PubMedGoogle Scholar
  107. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301(5638):1387–1391PubMedGoogle Scholar
  108. Mello C, Fire A (1995) DNA transformation. Methods Cell Biol 48:451–482PubMedGoogle Scholar
  109. Mello CC, Kramer JM, Stinchcomb D, Ambros V (1991) Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10(12):3959–3970PubMedGoogle Scholar
  110. Mucke L, Masliah E, Johnson WB, Ruppe MD, Alford M, Rockenstein EM, Forss-Petter S, Pietropaolo M, Mallory M, Abraham CR (1994) Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res 666(2):151–167. doi: 0006-8993(94)90767-6 PubMedGoogle Scholar
  111. Muller U, Cristina N, Li ZW, Wolfer DP, Lipp HP, Rulicke T, Brandner S, Aguzzi A, Weissmann C (1994) Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene. Cell 79(5):755–765. doi: 0092-8674(94)90066-3 PubMedGoogle Scholar
  112. Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424(6946):277–283PubMedGoogle Scholar
  113. Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254(5028):97–99PubMedGoogle Scholar
  114. Nagel G, Brauner M, Liewald JF, Adeishvili N, Bamberg E, Gottschalk A (2005) Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr Biol 15(24):2279–2284. doi: 10.1016/j.cub.2005.11.032 PubMedGoogle Scholar
  115. Nguyen M, Alfonso A, Johnson CD, Rand JB (1995) Caenorhabditis elegans mutants resistant to inhibitors of acetylcholinesterase. Genetics 140(2):527–535PubMedGoogle Scholar
  116. 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(7232):981–989PubMedGoogle Scholar
  117. Niwa R, Hada K (2010) Identification of a spatio-temporal enhancer element for the Alzheimer’s amyloid precursor protein-like-1 gene in the nematode Caenorhabditis elegans. Biosci Biotechnol Biochem 74(12):2497–2500. doi: JST.JSTAGE/bbb/100450 PubMedGoogle Scholar
  118. Niwa R, Zhou F, Li C, Slack FJ (2008) The expression of the Alzheimer’s amyloid precursor protein-like gene is regulated by developmental timing microRNAs and their targets in Caenorhabditis elegans. Dev Biol 315(2):418–425PubMedGoogle Scholar
  119. Nordstedt C, Caporaso GL, Thyberg J, Gandy SE, Greengard P (1993) Identification of the Alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells. J Biol Chem 268(1):608–612PubMedGoogle Scholar
  120. Nunan J, Small DH (2000) Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 483(1):6–10. doi: S0014-5793(00)02076-7 PubMedGoogle Scholar
  121. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389(6654):994–999PubMedGoogle Scholar
  122. Oliveira RP, Porter Abate J, Dilks K, Landis J, Ashraf J, Murphy CT, Blackwell TK (2009) Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 8(5):524–541. doi: 10.1111/j.1474-9726.2009.00501.x PubMedGoogle Scholar
  123. Paliga K, Peraus G, Kreger S, Durrwang U, Hesse L, Multhaup G, Masters CL, Beyreuther K, Weidemann A (1997) Human amyloid precursor-like protein 1-cDNA cloning, ectopic expression in COS-7 cells and identification of soluble forms in the cerebrospinal fluid. Eur J Biochem 250(2):354–363PubMedGoogle Scholar
  124. Park SK, Tedesco PM, Johnson TE (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging Cell 8(3):258–269. doi: 10.1111/j.1474-9726.2009.00473.x PubMedGoogle Scholar
  125. Rand JB, Russell RL (1985) Molecular basis of drug-resistance mutations in C. elegans. Psychopharmacol Bull 21(3):623–630PubMedGoogle Scholar
  126. Ranganathan S, Noyes NC, Migliorini M, Winkles JA, Battey FD, Hyman BT, Smith E, Yepes M, Mikhailenko I, Strickland DK (2011) LRAD3, A novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. J Neurosci 31(30):10836–10846. doi: 10.1523/JNEUROSCI.5065-10.2011 PubMedGoogle Scholar
  127. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403(6772):901–906. doi: 10.1038/35002607 PubMedGoogle Scholar
  128. Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M, Wolfer DP, Muller UC (2007) The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 27(29):7817–7826PubMedGoogle Scholar
  129. 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(6543):775–778PubMedGoogle Scholar
  130. 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 USA 86(7):2478–2482Google Scholar
  131. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38(1):24–26PubMedGoogle Scholar
  132. Sabo SL, Ikin AF, Buxbaum JD, Greengard P (2001) The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. J Cell Biol 153(7):1403–1414PubMedGoogle Scholar
  133. Salbaum JM, Ruddle FH (1994) Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. J Exp Zool 269(2):116–127. doi: 10.1002/jez.1402690205 PubMedGoogle Scholar
  134. Schupf N, Kapell D, Nightingale B, Rodriguez A, Tycko B, Mayeux R (1998) Earlier onset of Alzheimer’s disease in men with Down syndrome. Neurology 50(4):991–995PubMedGoogle Scholar
  135. Shaye DD, Greenwald I (2011) OrthoList: a compendium of C. elegans genes with human orthologs. PLoS One 6(5):e20085. doi: 10.1371/journal.pone.0020085PONE-D-11-05121 PubMedGoogle Scholar
  136. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760PubMedGoogle Scholar
  137. Singh R, Sulston J (1978) Some observations on molting in C. elegans. Nematologica 24(1):63–71Google Scholar
  138. Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C (2006) APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129(Pt 11):2977–2983PubMedGoogle Scholar
  139. Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS (1994) Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem 269(4):2637–2644PubMedGoogle Scholar
  140. Sprecher CA, Grant FJ, Grimm G, O’Hara PJ, Norris F, Norris K, Foster DC (1993) Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family. Biochemistry 32(17):4481–4486PubMedGoogle Scholar
  141. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis 7(1):63–80PubMedGoogle Scholar
  142. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 105(9):3438–3442. doi: 10.1073/pnas.0705467105 PubMedGoogle Scholar
  143. Sulston JE, Horvitz HR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1):110–156PubMedGoogle Scholar
  144. Sulston JE, White JG (1980) Regulation and cell autonomy during postembryonic development of Caenorhabditis elegans. Dev Biol 78(2):577–597PubMedGoogle Scholar
  145. Sulston J, Dew M, Brenner S (1975) Dopaminergic neurons in the nematode Caenorhabditis elegans. J Comp Neurol 163(2):215–226. doi: 10.1002/cne.901630207 PubMedGoogle Scholar
  146. Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100(1):64–119. doi: 0012-1606(83)90201-4 PubMedGoogle Scholar
  147. Sumakovic M, Hegermann J, Luo L, Husson SJ, Schwarze K, Olendrowitz C, Schoofs L, Richmond J, Eimer S (2009) UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation in Caenorhabditis elegans. J Cell Biol 186(6):897–914. doi: 10.1083/jcb.200902096 PubMedGoogle Scholar
  148. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature 422(6930):438–441. doi: 10.1038/nature01506nature01506 PubMedGoogle Scholar
  149. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292(5514):107–110PubMedGoogle Scholar
  150. Terry RD, Gonatas NK, Weiss M (1964) Ultrastructural studies in Alzheimer’s presenile dementia. Am J Pathol 44:269–297PubMedGoogle Scholar
  151. Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132(6):1025–1038. doi: 10.1016/j.cell.2008.01.030 PubMedGoogle Scholar
  152. Vargas T, Martinez-Garcia A, Antequera D, Vilella E, Clarimon J, Mateo I, Sanchez-Juan P, Rodriguez–Rodriguez E, Frank A, Rosich-Estrago M, Lleo A, Molina-Porcel L, Blesa R, Gomez-Isla T, Combarros O, Bermejo-Pareja F, Valdivieso F, Bullido MJ, Carro E (2011) IGF-I gene variability is associated with an increased risk for AD. Neurobiol Aging 32(3):556 e553-511. doi: 10.1016/j.neurobiolaging.2010.10.017 Google Scholar
  153. 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(5440):735–741. doi: 7936 PubMedGoogle Scholar
  154. von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, van der Ploeg LH, Price DL, Sisodia SS (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18(6):661–669Google Scholar
  155. von Otter M, Landgren S, Nilsson S, Zetterberg M, Celojevic D, Bergstrom P, Minthon L, Bogdanovic N, Andreasen N, Gustafson DR, Skoog I, Wallin A, Tasa G, Blennow K, Nilsson M, Hammarsten O, Zetterberg H (2010) Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer’s disease and age-related cataract. Mech Ageing Dev 131(2):105–110. doi: 10.1016/j.mad.2009.12.007 Google Scholar
  156. Wang Y, Ha Y (2004) The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 15(3):343–353PubMedGoogle Scholar
  157. Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci USA 89(22):10758–10762PubMedGoogle Scholar
  158. Wasco W, Gurubhagavatula S, Paradis MD, Romano DM, Sisodia SS, Hyman BT, Neve RL, Tanzi RE (1993a) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet 5(1):95–100. doi: 10.1038/ng0993-95 PubMedGoogle Scholar
  159. Wasco W, Peppercorn J, Tanzi RE (1993b) Search for the genes responsible for familial Alzheimer’s disease. Ann N Y Acad Sci 695:203–208PubMedGoogle Scholar
  160. Westlund B, Parry D, Clover R, Basson M, Johnson CD (1999) Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling. Proc Natl Acad Sci U S A 96(5):2497–2502PubMedGoogle Scholar
  161. Wheelan SJ, Boguski MS, Duret L, Makalowski W (1999) Human and nematode orthologs–lessons from the analysis of 1800 human genes and the proteome of Caenorhabditis elegans. Gene 238(1):163–170. doi: S0378-1119(99)00298-X PubMedGoogle Scholar
  162. White JG, Southgate E, Thomson JN, Brenner S (1986) The structure of the nervous system of the nematode C. elegans. Philos Trans Roy Soc Lond Ser B Biol Sci 314(1165):1–340Google Scholar
  163. Wiese M, Antebi A, Zheng H (2010) Intracellular trafficking and synaptic function of APL-1 in Caenorhabditis elegans. PLoS One 5(9). doi: 10.1371/journal.pone.0012790
  164. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105(37):13987–13992. doi: 10.1073/pnas.0801030105 PubMedGoogle Scholar
  165. Wirths O, Multhaup G, Czech C, Blanchard V, Moussaoui S, Tremp G, Pradier L, Beyreuther K, Bayer TA (2001) Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett 306(1–2):116–120. doi: S0304-3940(01)01876-6 PubMedGoogle Scholar
  166. Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26(50):13102–13113PubMedGoogle Scholar
  167. Xu K, Tavernarakis N, Driscoll M (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum. Neuron 31(6):957–971. doi: S0896-6273(01)00432-9 PubMedGoogle Scholar
  168. Yamada T, Sasaki H, Furuya H, Miyata T, Goto I, Sakaki Y (1987) Complementary DNA for the mouse homolog of the human amyloid beta protein precursor. Biochem Biophys Res Commun 149(2):665–671. doi: 0006-291X(87)90419-0 PubMedGoogle Scholar
  169. Yochem J, Tuck S, Greenwald I, Han M (1999) A gp330/megalin-related protein is required in the major epidermis of Caenorhabditis elegans for completion of molting. Development 126(3):597–606PubMedGoogle Scholar
  170. 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(6800):48–54. doi: 10.1038/35024009 PubMedGoogle Scholar
  171. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75(4):641–652. doi: 0092-8674(93)90485-9 PubMedGoogle Scholar
  172. Zambrano N, Bimonte M, Arbucci S, Gianni D, Russo T, Bazzicalupo P (2002) feh-1 and apl-1, the Caenorhabditis elegans orthologues of mammalian Fe65 and beta-amyloid precursor protein genes, are involved in the same pathway that controls nematode pharyngeal pumping. J Cell Sci 115(Pt 7):1411–1422PubMedGoogle Scholar
  173. Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW, Stevens KA, Slunt HH, Sisoda SS, Chen HY, Van der Ploeg LH (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81(4):525–531PubMedGoogle Scholar

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© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Graduate CenterCity University of New YorkNew YorkUSA
  2. 2.Department of BiologyCity College of New YorkNew YorkUSA

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