The development of an in vivo γ-secretase assay using zebrafish embryos

Journal of Alzheimer's Disease

Volumn 36, Issue 3, 2013, Pages 521-534

  Wilson, Lachlan ^a   Lardelli, Michael ^a  

^a UNIVERSITY OF ADELAIDE   (Australia)

Author keywords

Alzheimer's disease; amyloid protein precursor; assay; morpholinos; presenilin; truncated protein; zebrafish; secretase

Indexed keywords

GAMMA SECRETASE;

ARTICLE; CONTROLLED STUDY; EMBRYO; ENZYME ACTIVITY; ENZYME ASSAY; IN VIVO STUDY; NONHUMAN; PRIORITY JOURNAL; WESTERN BLOTTING; ZEBRA FISH;

EID: 84881427117     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-130332     Document Type: Article

References (144)

1. Tanzi RE, BertramL(2005)Twenty years of the Alzheimer's disease amyloid hypothesis:Agenetic perspective. Cell 120, 545-555
2. Hardy JA, Higgins GA (1992) Alzheimer's disease: The amyloid cascade hypothesis. Science 256, 184-185
3. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 297, 353-356
4. Haass C, Selkoe DJ (1993) Cellular processing of betaamyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75, 1039-1042
5. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37, 925-937
6. Dyrks T,Weidemann A, Multhaup G, Salbaum JM, Lemaire HG, Kang J, Muller-Hill B, Masters CL, Beyreuther K (1988) Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J 7, 949-957
7. Busciglio J, Gabuzda DH, Matsudaira P,Yankner BA(1993) Generation of beta-Amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A 90, 2092-2096
8. Higaki J, Quon D, Zhong Z, Cordell B (1995) Inhibition of beta-Amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651-659
9. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387-390
10. Tarassishin L, Yin YI, Bassit B, LiYM(2004) Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct. Proc Natl Acad Sci U S A 101, 17050-17055
11. Chyung JH, Raper DM, Selkoe DJ (2005) Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. J Biol Chem 280, 4383-4392
12. Wolfe MS, De Los Angeles J, Miller DD, XiaW, Selkoe DJ (1999) Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry 38, 11223-11230
13. 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
14. Goutte C, Tsunozaki M, Hale VA, Priess JR (2002) APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 99, 775-779
15. Lee SF, Shah S, Li H,Yu C, HanW,YuG(2002) Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem 277, 45013-45019
16. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, XuW, 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, 85-97
17. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, Kostka M, Haass C (2002) PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 277, 39062-39065
18. Haass C, Steiner H (2002) Alzheimer disease gammasecretase: A complex story of GxGD-type presenilin proteases. Trends Cell Biol 12, 556-562
19. De Strooper B (2003) Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38, 9-12
20. Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y (2001) Distinct intramembrane cleavage of the beta-Amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem 276, 35235-35238
21. Yu C, Kim SH, Ikeuchi T, Xu H, Gasparini L, Wang R, Sisodia SS (2001) Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma-secretase processing of the APP and Notch1 transmembrane domains. J Biol Chem 276, 43756-43760
22. Zhao G, Mao G, Tan J, Dong Y, Cui MZ, Kim SH, Xu X (2004) Identification of a new presenilin-dependent zetacleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 279, 50647-50650
23. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, Teplow DB, Haass C (2001) Presenilindependent gamma-secretase processing of beta-Amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Reports 2, 835-841
24. Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G (2002) A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825-2835
25. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron 13, 45-53
26. Jarrett JT, Berger EP, Lansbury PT, Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693-4697
27. Jarrett JT, Lansbury PT, Jr (1993) Seeding "one-dimensional crystallization" of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055-1058
28. Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, Kirschner DA (1992) Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry 31, 10716-10723
29. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW (1993) Neurodegeneration induced by beta-Amyloid peptides in vitro: The role of peptide assembly state. J Neurosci 13, 1676-1687
30. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y (2005) Longer forms of amyloid beta protein: Implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci 25, 436-445
31. Rodriguez-Manotas M, Amorin-Diaz M, Cabezas-Herrera J, Acedo-Martinez A, Llorca-Escuin I (2012) Are gammasecretase and its associated Alzheimer's disease gamma problems? Med Hypotheses 78, 299-304
32. Xu X (2009) Gamma-secretase catalyzes sequential cleavages of the AbetaPP transmembrane domain. J Alzheimers Dis 16, 211-224
33. Klafki H, Abramowski D, Swoboda R, Paganetti PA, StaufenbielM(1996) The carboxyl termini of beta-Amyloid peptides 1-40 and 1-42 are generated by distinct gammasecretase activities. J Biol Chem 271, 28655-28659
34. Citron M, Diehl TS, Gordon G, Biere AL, Seubert P, Selkoe DJ (1996) Evidence that the 42-And 40-Amino acid forms of amyloid beta protein are generated from the beta-Amyloid precursor protein by different protease activities. Proc Natl Acad Sci U S A 93, 13170-13175
35. Zhao G, Tan J, Mao G, Cui MZ, Xu X (2007) The same gamma-secretase accounts for the multiple intramembrane cleavages of APP. J Neurochem 100, 1234-1246
36. McCarthy JV, Twomey C, Wujek P (2009) Presenilindependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 66, 1534-1555
37. Haapasalo A, Kovacs DM (2011) The many substrates of presenilin/gamma- secretase. J Alzheimers Dis 25, 3-28
38. Hemming ML, Elias JE, Gygi SP, Selkoe DJ (2008) Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol 6, e257
39. Cowburn RF, Popescu BO, Ankarcrona M, Dehvari N, Cedazo-Minguez A (2007) Presenilin-mediated signal transduction. Physiol Behav 92, 93-97
40. McCarthy JV (2005) Involvement of presenilins in cellsurvival signalling pathways. Biochem Soc Trans 33, 568-572
41. Annaert W, De Strooper B (1999) Presenilins: Molecular switches between proteolysis and signal transduction. Trends Neurosci 22, 439-443
42. Koo EH, Kopan R (2004) Potential role of presenilinregulated signaling pathways in sporadic neurodegeneration. Nat Med 10 Suppl, S26-33
43. Raurell I, Castano J, Franci C, Garcia de Herreros A, Dunach M (2006) Presenilin-1 interacts with plakoglobin and enhances plakoglobin-Tcf-4 association. Implications for the regulation of beta-catenin/Tcf-4-dependent transcription. J Biol Chem 281, 1401-1411
44. Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK (2004) PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutations. EMBO J 23, 2586-2596
45. Dewachter I, Ris L, Croes S, Borghgraef P, Devijver H,Voets T, Nilius B, Godaux E, Van Leuven F (2008) Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1. Neurobiol Aging 29, 639-652
46. Feng R,Wang H,Wang J, Shrom D, Zeng X, Tsien JZ (2004) Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2. Proc Natl Acad Sci U S A 101, 8162-8167
47. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ, 3rd, Kandel ER, DuffK, Kirkwood A, Shen J (2004) Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23-36
48. Zhu M, Gu F, Shi J, Hu J, Hu Y, Zhao Z (2008) Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2. Free Radic Biol Med 45, 1493-1499
49. Takahashi N, Kariya S, Hirano M, Ueno S (2003) Two novel spliced presenilin 2 transcripts in human lymphocyte with oxidant stress and brain. Mol Cell Biochem 252, 279-283
50. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat Rev Neurosci 3, 862-872
51. Mattson MP (2010) ER calcium and Alzheimer's disease: In a state of flux. Sci Signal 3, pe10
52. Cook DG, Li X, Cherry SD, Cantrell AR (2005) Presenilin 1 deficiency alters the activity of voltage-gated Ca2+channels in cultured cortical neurons. J Neurophysiol 94, 4421-4429
53. Leissring MA, AkbariY, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149, 793-798
54. Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, XiaW, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, Kim TW (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561-572
55. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM (2008) SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol 181, 1107-1116
56. Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58, 871-883
57. Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J Neurosci 26, 5180-5189
58. Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK (2010) Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's diseaselinked presenilin mutants in human cells and mouse neurons. Sci Signal 3, ra22
59. Zatti G, Burgo A, Giacomello M, Barbiero L, Ghidoni R, Sinigaglia G, Florean C, Bagnoli S, Binetti G, Sorbi S, Pizzo P, Fasolato C (2006) Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium 39, 539-550
60. Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I (2007) Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Investig 117, 1230-1239
61. Shen J, Kelleher RJ, 3rd (2007) The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A 104, 403-409
62. Michno K, Knight D, Campusano JM, van de Hoef D, BoulianneGL (2009) Intracellular calcium deficits in Drosophila cholinergic neurons expressing wild type or FAD-mutant presenilin. PLoS One 4, e6904
63. Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F (2003) Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem 278, 2484-2489
64. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM,Wolfe DM, Martinez-Vicente M, MasseyAC, SovakG, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146-1158
65. Williamson WR, Hiesinger PR (2010) On the role of v-ATPase V0a1-dependent degradation in Alzheimer disease. Commun Integr Biol 3, 604-607
66. Neely KM, Green KN, LaFerla FM (2011) Presenilin is necessary for efficient proteolysis through the autophagylysosome system in a gamma-secretase-independent manner. J Neurosci 31, 2781-2791
67. Neely KM, Green KN (2011) Presenilins mediate efficient proteolysis via the autophagosome-lysosome system. Autophagy 7, 664-665
68. 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, BruniAC,MontesiMP, 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
69. Saura CA, Servian-Morilla E, Scholl FG (2011) Presenilin/ gamma-secretase regulates neurexin processing at synapses. PLoS One 6, e19430
70. Kunimoto S, Nakamura S,Wada K, Inoue T (2010) Chronic stress-mutated presenilin 1 gene interaction perturbs neurogenesis and accelerates neurodegeneration. Exp Neurol 221, 175-185
71. Barthet G, Dunys J, Shao Z, Xuan Z, Ren Y, Xu J, Arbez N, Mauger G, Bruban J, Georgakopoulos A, Shioi J, Robakis NK (2013) Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 34, 499-510
72. Shvartsman AL, Sarantseva SV, Vitek MP (2011) [Potential role of presenilin 1 in regulation of synaptic function]. Tsitologiia 53, 959-967
73. Ho A, Shen J (2011) Presenilins in synaptic function and disease. Trends Mol Med 17, 617-624
74. Supnet C, Bezprozvanny I (2011) Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis. Cell Calcium 50, 303-309
75. Chan SL, Culmsee C, Haughey N, Klapper W, Mattson MP(2002) Presenilin-1 mutations sensitize neurons toDNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. Neurobiol Dis 11, 2-19
76. McLendon C, Xin T, Ziani-Cherif C, Murphy MP, Findlay KA, Lewis PA, Pinnix I, Sambamurti K, Wang R, Fauq A, Golde TE (2000) Cell-free assays for gamma-secretase activity. FASEB J 14, 2383-2386
77. Czech C, Burns MP, Vardanian L, Augustin A, Jacobsen H, Baumann K, Rebeck GW (2007) Cholesterol independent effect of LXR agonist TO-901317 on gamma-secretase. J Neurochem 101, 929-936
78. Hoke DE, Tan JL, Ilaya NT, Culvenor JG, Smith SJ, White AR, Masters CL, EvinGM(2005) In vitro gamma-secretase cleavage of the Alzheimer's amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc. FEBS J 272, 5544-5557
79. Kim SK, Park HJ, Hong HS, Baik EJ, JungMW,Mook-Jung I (2006) ERK1/2 is an endogenous negative regulator of the gamma-secretase activity. FASEB J 20, 157-159
80. Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ (2000) Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci U S A 97, 6138-6143
81. Sernee MF, Evin G, Culvenor JG, Villadangos JA, Beyreuther K, Masters CL, Cappai R (2003) Selecting cells with different Alzheimer's disease gamma-secretase activity using FACS. Differential effect on presenilin exon 9 gammaand epsilon-cleavage. Eur J Biochem 270, 495-506
82. Karlstrom H, Bergman A, Lendahl U, Naslund J, Lundkvist J (2002) A sensitive and quantitative assay for measuring cleavage of presenilin substrates. J Biol Chem 277, 6763-6766
83. Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS (2004) Tumor necrosis factor-Alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNKdependentMAPKpathway. J Biol Chem 279, 49523-49532
84. Yagishita S, Futai E, Ishiura S (2008) In vitro reconstitution of gamma-secretase activity using yeast microsomes. Biochem Biophys Res Commun 377, 141-145
85. Leimer U, Lun K, Romig H,Walter J, Grunberg J, Brand M, Haass C (1999) Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta-peptide production and requires a critical aspartate residue for its function in amyloidogenesis. Biochemistry 38, 13602-13609
86. Groth C, Nornes S, McCarty R, Tamme R, LardelliM(2002) Identification of a second presenilin gene in zebrafish with similarity to the human Alzheimer's disease gene presenilin2. Dev Genes Evol 212, 486-490
87. Newman M, Musgrave IF, LardelliM(2007) Alzheimer disease: Amyloidogenesis, the presenilins and animal models. Biochim Biophys Acta 1772, 285-297
88. Nornes S, Groth C, Camp E, Ey P, Lardelli M (2003) Developmental control of Presenilin1 expression, endoproteolysis, and interaction in zebrafish embryos. Exp Cell Res 289, 124-132
89. Musa A, Lehrach H, Russo VA (2001) Distinct expression patterns of two zebrafish homologues of the human APP gene during embryonic development. Dev Genes Evol 211, 563-567
90. Joshi P, Liang JO, DiMonte K, Sullivan J, Pimplikar SW (2009) Amyloid precursor protein is required for convergent-extension movements during Zebrafish development. Dev Biol 335, 1-11
91. Fang G, Weiser B, Visosky A, Moran T, Burger H (1999) PCR-mediated recombination: A general method applied to construct chimeric infectious molecular clones of plasmaderived HIV-1 RNA. Nat Med 5, 239-242
92. Barash S, Wang W, Shi Y (2002) Human secretory signal peptide description by hidden Markov model and generation of a strong artificial signal peptide for secreted protein expression. Biochem Biophys Res Commun 294, 835-842
93. Nornes S, Newman M, Verdile G, Wells S, Stoick-Cooper CL, Tucker B, Frederich-Sleptsova I, Martins R, LardelliM (2008) Interference with splicing of Presenilin transcripts has potent dominant negative effects on Presenilin activity. Hum Mol Genet 17, 402-412
94. Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, De Strooper B, Annaert W (2001) The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J Cell Biol 154, 731-740
95. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: The role of the disintegrin-metalloprotease TACE. Mol Cell 5, 207-216
96. MummJS, Schroeter EH, SaxenaMT, Griesemer A, Tian X, Pan DJ, Ray WJ,KopanR(2000)Aligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5, 197-206
97. Struhl G, Adachi A (2000) Requirements for presenilindependent cleavage of notch and other transmembrane proteins. Mol Cell 6, 625-636
98. Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M (2008) Oxidative stress activates a positive feedback between the gamma-And betasecretase cleavages of the beta-Amyloid precursor protein. J Neurochem 104, 683-695
99. Lichtenthaler SF, Multhaup G, Masters CL, Beyreuther K (1999) A novel substrate for analyzing Alzheimer's disease gamma-secretase. FEBS Lett 453, 288-292
100. Zhang C, Khandelwal PJ, Chakraborty R, Cuellar TL, Sarangi S, Patel SA, Cosentino CP, O'Connor M, Lee JC, Tanzi RE, Saunders AJ (2007) An AICD-based functional screen to identify APP metabolism regulators. Mol Neurodegener 2, 15
101. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M (2005) Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of betaamyloid precursor protein carboxy-terminal fragment. J Neurochem 94, 1189-1201
102. Marlow L, Cain M, Pappolla MA, Sambamurti K (2003) Beta-secretase processing of the Alzheimer's amyloid protein precursor (APP). J Mol Neurosci 20, 233-239
103. Almkvist O, Basun H, Wagner SL, Rowe BA, Wahlund LO, Lannfelt L (1997) Cerebrospinal fluid levels of alphasecretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch Neurol 54, 641-644
104. Kobayashi DT, Chen KS (2005) Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's disease. Genes Brain Behav 4, 173-196
105. Puig KL, CombsCK(2012) Expression and function of APP and its metabolites outside the central nervous system. Exp Gerontol, doi: 10.1016/j.exger.2012.07. 009
106. Marchesi VT (2012) Alzheimer's disease 2012: The great amyloid gamble. Am J Pathol 180, 1762-1767
107. ReitzC(2012) Alzheimer's disease and the amyloid cascade hypothesis: A critical review. Int J Alzheimers Dis 2012, 369808
108. Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA (2009) Reexamining Alzheimer's disease: Evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 18, 447-452
109. Hunter S, Brayne C (2012) Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems. Alzheimers Res Therap 4, 10
110. Kogel D, Concannon CG, Muller T, Konig H, Bonner C, Poeschel S, Chang S, Egensperger R, Prehn JH (2012) The APP intracellular domain (AICD) potentiates ER stressinduced apoptosis. Neurobiol Aging 33, 2200-2209
111. Passer B, Pellegrini L, Russo C, Siegel RM, Lenardo MJ, Schettini G, Bachmann M, Tabaton M, D'Adamio L (2000) Generation of an apoptotic intracellular peptide by gammasecretase cleavage of Alzheimer's amyloid beta protein precursor. J Alzheimers Dis 2, 289-301
112. 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
113. Chen WJ, Goldstein JL, Brown MS (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 265, 3116-3123
114. Koo EH, Squazzo SL (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 269, 17386-17389
115. Lai A, Sisodia SS, Trowbridge IS (1995) Characterization of sorting signals in the beta-Amyloid precursor protein cytoplasmic domain. J Biol Chem 270, 3565-3573
116. Kim HS, Kim EM, Lee JP, Park CH, Kim S, Seo JH, Chang KA, Yu E, Jeong SJ, Chong YH, Suh YH (2003) C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression. FASEB J 17, 1951-1953
117. Shaked GM, Kummer MP, Lu DC, Galvan V, Bredesen DE, KooEH(2006) Abeta induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597-624). FASEB J 20, 1254-1256
118. McPhie DL, Golde T, Eckman CB, Yager D, Brant JB, Neve RL (2001) Beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations. Brain Res Mol Brain Res 97, 103-113
119. Dyrks T, Dyrks E, Monning U, Urmoneit B, Turner J, Beyreuther K (1993) Generation of beta A4 from the amyloid protein precursor and fragments thereof. FEBS Lett 335, 89-93
120. 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
121. Edbauer D, Willem M, Lammich S, Steiner H, Haass C (2002) Insulin-degrading enzyme rapidly removes the betaamyloid precursor protein intracellular domain (AICD). J Biol Chem 277, 13389-13393
122. Venugopal C, Pappolla MA, SambamurtiK(2007) Insulysin cleaves the APP cytoplasmic fragment at multiple sites. Neurochem Res 32, 2225-2234
123. FarrisW, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-Amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100, 4162-4167
124. Nunan J, Shearman MS, Checler F, Cappai R, Evin G, Beyreuther K, Masters CL, SmallDH(2001) The C-terminal fragment of the Alzheimer's disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase. Eur J Biochem 268, 5329-5336
125. Shirotani K, Edbauer D, Prokop S, Haass C, SteinerH(2004) Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 279, 41340-41345
126. Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horre K, Van Houtvin T, Esselmann H, Paul S, Schafer MK, Berezovska O, Hyman BT, Sprangers B, Sciot R, Moons L, Jucker M, Yang Z, May PC, Karran E,Wiltfang J, D'Hooge R, De Strooper B (2009) Gamma-Secretase heterogeneity in the Aph1 subunit: Relevance for Alzheimer's disease. Science 324, 639-642
127. Hebert SS, Serneels L, Dejaegere T, Horre K, Dabrowski M, Baert V, Annaert W, Hartmann D, De Strooper B (2004) Coordinated and widespread expression of gamma-secretase in vivo: Evidence for size and molecular heterogeneity. Neurobiol Dis 17, 260-272
128. Herreman A, Serneels L, AnnaertW, Collen D, Schoonjans L, De Strooper B (2000) Total inactivation of gammasecretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2, 461-462
129. Herreman A, Hartmann D, AnnaertW, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96, 11872-11877
130. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA (2000) Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2, 463-465
131. Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13, 2801-2810
132. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689-694
133. Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD (2010) Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143-1154
134. Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J, Lee M, Hu K, Schenk D, Yednock T, Basi G (2008) Identification of gamma-secretase inhibitor potency determinants on presenilin. J Biol Chem 283, 2927-2938
135. Lee J, Song L, Terracina G, Bara T, Josien H, Asberom T, Sasikumar TK, Burnett DA, Clader J, Parker EM, Zhang L (2011) Identification of presenilin 1-selective gammasecretase inhibitors with reconstituted gamma-secretase complexes. Biochemistry 50, 4973-4980
136. Shen J, Bronson RT, Chen DF, XiaW, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629-639
137. Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288-292
138. Franberg J, Svensson AI,Winblad B, Karlstrom H, Frykman S (2011) Minor contribution of presenilin 2 for gammasecretase activity in mouse embryonic fibroblasts and adult mouse brain. Biochem Biophys Res Commun 404, 564-568
139. LaiMT, Chen E, CrouthamelMC,DiMuzio-Mower J,XuM, Huang Q, Price E, Register RB, Shi XP, Donoviel DB, Bernstein A, Hazuda D, Gardell SJ, Li YM (2003) Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gammasecretase activities. J Biol Chem 278, 22475-22481
140. Yonemura Y, Futai E, Yagishita S, Suo S, Tomita T, Iwatsubo T, Ishiura S (2011) Comparison of presenilin 1 and presenilin 2 gamma-secretase activities using a yeast reconstitution system. J Biol Chem 286, 44569-44575
141. Jayadev S, Case A, Eastman AJ, Nguyen H, Pollak J,Wiley JC, Moller T, Morrison RS, Garden GA (2010) Presenilin 2 is the predominant gamma-secretase in microglia and modulates cytokine release. PLoS One 5, e15743
142. Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol 175, 1810-1816
143. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M (2005) Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of betaamyloid precursor protein carboxy-terminal fragment. J Neurochem 94, 1189-1201
144. Barbagallo AP, Wang Z, Zheng H, D'Adamio L (2011) A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J Biol Chem 286, 8717-8721