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Acta Neuropathologica

, Volume 129, Issue 1, pp 1–19 | Cite as

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

  • Hoang S. Nhan
  • Karen Chiang
  • Edward H. Koo
Review

Abstract

The amyloid precursor protein (APP) has occupied a central position in Alzheimer’s disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP’s involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPβ), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the –YENPTY– motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.

Keywords

Alzheimer’s disease (AD) Amyloid precursor protein (APP) Amyloid-β peptide (Aβ) Caspases C31 YENPTY 

Notes

Acknowledgments

This work was supported in part by NIH Grants AG000216 (NH, KC), AG20206 (EHK), and NS84324 (EHK); NMRC/STaR 009/2012 (EHK).

References

  1. 1.
    Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I (2009) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 12(12):1567–1576PubMedGoogle Scholar
  2. 2.
    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
  3. 3.
    Allinson TM, Parkin ET, Turner AJ, Hooper NM (2003) ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74(3):342–352PubMedGoogle Scholar
  4. 4.
    Almkvist O, Basun H, Wagner SL, Rowe BA, Wahlund LO, Lannfelt L (1997) Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch Neurol 54(5):641–644PubMedGoogle Scholar
  5. 5.
    Anderson JJ, Holtz G, Baskin PP, Wang R, Mazzarelli L, Wagner SL, Menzaghi F (1999) Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits. Neuroscience 93(4):1409–1420PubMedGoogle Scholar
  6. 6.
    Araki W, Kitaguchi N, Tokushima Y, Ishii K, Aratake H, Shimohama S, Nakamura S, Kimura J (1991) Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun 181(1):265–271PubMedGoogle Scholar
  7. 7.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776PubMedGoogle Scholar
  8. 8.
    Austin SA, Combs CK (2008) Mechanisms of microglial activation by amyloid precursor protein and its proteolytic fragments. In: Lane TE, Carson M, Bergmann C, Wyss-Coray T (eds) Central nervous system diseases and inflammation, 2008th edn. Springer, New York, pp 13–32Google Scholar
  9. 9.
    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(1):55–67PubMedGoogle Scholar
  10. 10.
    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(11):8717–8721PubMedCentralPubMedGoogle Scholar
  11. 11.
    Barbagallo AP, Weldon R, Tamayev R, Zhou D, Giliberto L, Foreman O, D’Adamio L (2010) Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo. PLoS One 5(11):e15503PubMedCentralPubMedGoogle Scholar
  12. 12.
    Barger SW, Harmon AD (1997) Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388(6645):878–881PubMedGoogle Scholar
  13. 13.
    Barnes NY, Li L, Yoshikawa K, Schwartz LM, Oppenheim RW, Milligan CE (1998) Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons. J Neurosci 18(15):5869–5880PubMedGoogle Scholar
  14. 14.
    Bayer TA, Wirths O (2014) Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer’s disease. Acta Neuropathol 127(6):787–801PubMedCentralPubMedGoogle Scholar
  15. 15.
    Berger-Sweeney J, McPhie DL, Arters JA, Greenan J, Oster-Granite ML, Neve RL (1999) Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Mol Brain Res 66(1–2):150–162PubMedGoogle Scholar
  16. 16.
    Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci 14(6):750–756PubMedCentralPubMedGoogle Scholar
  17. 17.
    Bertrand E, Brouillet E, Caille I, Bouillot C, Cole GM, Prochiantz A, Allinquant B (2001) A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo. Mol Cell Neurosci 18(5):503–511PubMedGoogle Scholar
  18. 18.
    Boon WC, van den Buuse M, Wegener N, Martin S, Chua HK, Bush AI, Masters CL, Adlard PA, Li QX (2010) Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Abeta-bearing fragment is associated with reduced NMDA receptor density. Behav Brain Res 209(1):27–35PubMedGoogle Scholar
  19. 19.
    Bredesen DE (2009) Neurodegeneration in Alzheimer’s disease: caspases and synaptic element interdependence. Mol Neurodegener 4:27PubMedCentralPubMedGoogle Scholar
  20. 20.
    Bredesen DE, John V, Galvan V (2010) Importance of the caspase cleavage site in amyloid-beta protein precursor. J Alzheimers Dis 22(1):57–63PubMedCentralPubMedGoogle Scholar
  21. 21.
    Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25(34):7709–7717PubMedGoogle Scholar
  22. 22.
    Cao X, Sudhof TC (2001) A transcriptionally (correction of transcriptively) active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293(5527):115–120PubMedGoogle Scholar
  23. 23.
    Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, Carlson EJ, Staufenbiel M, Nixon RA (2003) App gene dosage modulates endosomal abnormalities of Alzheimer’s disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci 23(17):6788–6792PubMedGoogle Scholar
  24. 24.
    Chasseigneaux S, Allinquant B (2012) Functions of Abeta, sAPPalpha and sAPPbeta : similarities and differences. J Neurochem 120(Suppl 1):99–108PubMedGoogle Scholar
  25. 25.
    Chen Y, Dong C (2009) Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ 16(3):386–394PubMedGoogle Scholar
  26. 26.
    Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58(1):42–51PubMedCentralPubMedGoogle Scholar
  27. 27.
    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(5):1168–1178PubMedGoogle Scholar
  28. 28.
    De Chiara G, Marcocci ME, Civitelli L, Argnani R, Piacentini R, Ripoli C, Manservigi R, Grassi C, Garaci E, Palamara AT (2010) APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells. PLoS One 5(11):e13989PubMedCentralPubMedGoogle Scholar
  29. 29.
    Dulin F, Leveille F, Ortega JB, Mornon JP, Buisson A, Callebaut I, Colloc’h N (2008) P3 peptide, a truncated form of A beta devoid of synaptotoxic effect, does not assemble into soluble oligomers. FEBS Lett 582(13):1865–1870PubMedGoogle Scholar
  30. 30.
    Fraser SP, Suh YH, Chong YH, Djamgoz MB (1996) Membrane currents induced in Xenopus oocytes by the C-terminal fragment of the beta-amyloid precursor protein. J Neurochem 66(5):2034–2040PubMedGoogle Scholar
  31. 31.
    Fukuchi K, Ho L, Younkin SG, Kunkel DD, Ogburn CE, LeBoeuf RC, Furlong CE, Deeb SS, Nochlin D, Wegiel J, Wisniewski HM, Martin GM (1996) High levels of circulating beta-amyloid peptide do not cause cerebral beta-amyloidosis in transgenic mice. Am J Pathol 149(1):219–227PubMedCentralPubMedGoogle Scholar
  32. 32.
    Fukuchi KI, Kunkel DD, Schwartzkroin PA, Kamino K, Ogburn CE, Furlong CE, Martin GM (1994) Overexpression of a C-terminal portion of the beta-amyloid precursor protein in mouse brains by transplantation of transformed neuronal cells. Exp Neurol 127(2):253–264PubMedGoogle Scholar
  33. 33.
    Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67(5):1882–1896PubMedGoogle Scholar
  34. 34.
    Galvan V, Chen S, Lu D, Logvinova A, Goldsmith P, Koo EH, Bredesen DE (2002) Caspase cleavage of members of the amyloid precursor family of proteins. J Neurochem 82(2):283–294PubMedGoogle Scholar
  35. 35.
    Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA, Bredesen DE (2006) Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci 103(18):7130–7135PubMedCentralPubMedGoogle Scholar
  36. 36.
    Galvan V, Zhang J, Gorostiza OF, Banwait S, Huang W, Ataie M, Tang H, Bredesen DE (2008) Long-term prevention of Alzheimer’s disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664. Behav Brain Res 191(2):246–255PubMedCentralPubMedGoogle Scholar
  37. 37.
    Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97(3):395–406PubMedGoogle Scholar
  38. 38.
    Ghosal K, Pimplikar SW (2011) Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice. Neurobiol Aging 32(12):2321–2329Google Scholar
  39. 39.
    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 106(43):18367–18372PubMedCentralPubMedGoogle Scholar
  40. 40.
    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):e11609PubMedCentralPubMedGoogle Scholar
  41. 41.
    Giliberto L, Zhou D, Weldon R, Tamagno E, De Luca P, Tabaton M, D’Adamio L (2008) Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a “regulated” transcriptional role. Mol Neurodegener 3:12PubMedCentralPubMedGoogle Scholar
  42. 42.
    Gowing E, Roher AE, Woods AS, Cotter RJ, Chaney M, Little SP, Ball MJ (1994) Chemical characterization of A beta 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J Biol Chem 269(15):10987–10990PubMedGoogle Scholar
  43. 43.
    Guo Q, Wang Z, Li H, Wiese M, Zheng H (2012) APP physiological and pathophysiological functions: insights from animal models. Cell Res 22(1):78–89PubMedCentralPubMedGoogle Scholar
  44. 44.
    Hansel DE, Rahman A, Wehner S, Herzog V, Yeo CJ, Maitra A (2003) Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 63(21):7032–7037PubMedGoogle Scholar
  45. 45.
    Harada J, Sugimoto M (1999) Activation of caspase-3 in beta-amyloid-induced apoptosis of cultured rat cortical neurons. Brain Res 842(2):311–323PubMedGoogle Scholar
  46. 46.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185PubMedGoogle Scholar
  47. 47.
    Harris JA, Devidze N, Halabisky B, Lo I, Thwin MT, Yu GQ, Bredesen DE, Masliah E, Mucke L (2010) Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer’s disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci 30(1):372–381PubMedCentralPubMedGoogle Scholar
  48. 48.
    Hoey SE, Williams RJ, Perkinton MS (2009) Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci 29(14):4442–4460PubMedGoogle Scholar
  49. 49.
    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 104(6):1971–1976PubMedCentralPubMedGoogle Scholar
  50. 50.
    Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S (2013) A DR6/p75(NTR) complex is responsible for beta-amyloid-induced cortical neuron death. Cell Death Dis 4:e579PubMedCentralPubMedGoogle Scholar
  51. 51.
    Itoh H, Kataoka H, Koita H, Nabeshima K, Inoue T, Kangawa K, Koono M (1991) Establishment of a new human cancer cell line secreting protease nexin-II/amyloid beta protein precursor derived from squamous-cell carcinoma of lung. Int J Cancer 49(3):436–443PubMedGoogle Scholar
  52. 52.
    Ivins KJ, Bui ET, Cotman CW (1998) Beta-amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis. Neurobiol Dis 5(5):365–378PubMedGoogle Scholar
  53. 53.
    Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ (1996) Full-length amyloid-beta [1-42(43)] and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol 149(6):1823–1830PubMedCentralPubMedGoogle Scholar
  54. 54.
    Jager S, Leuchtenberger S, Martin A, Czirr E, Wesselowski J, Dieckmann M, Waldron E, Korth C, Koo EH, Heneka M, Weggen S, Pietrzik CU (2009) alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation. J Neurochem 111(6):1369–1382PubMedGoogle Scholar
  55. 55.
    Jin LW, Hearn MG, Ogburn CE, Dang N, Nochlin D, Ladiges WC, Martin GM (1998) Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis. Am J Pathol 153(6):1679–1686PubMedCentralPubMedGoogle Scholar
  56. 56.
    Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T (1994) Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14(9):5461–5470PubMedGoogle Scholar
  57. 57.
    Kallop DY, Meilandt WJ, Gogineni A, Easley-Neal C, Wu T, Jubb AM, Yaylaoglu M, Shamloo M, Tessier-Lavigne M, Scearce-Levie K, Weimer RM (2014) A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer’s disease-related pathophysiology in murine models. J Neurosci 34(19):6425–6437PubMedGoogle Scholar
  58. 58.
    Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37(6):925–937PubMedGoogle Scholar
  59. 59.
    Kammesheidt A, Boyce FM, Spanoyannis AF, Cummings BJ, Ortegon M, Cotman C, Vaught JL, Neve RL (1992) Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci 89(22):10857–10861PubMedCentralPubMedGoogle Scholar
  60. 60.
    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(13):1951–1953PubMedGoogle Scholar
  61. 61.
    Kim HS, Lee JH, Suh YH (1999) C-terminal fragment of Alzheimer’s amyloid precursor protein inhibits sodium/calcium exchanger activity in SK-N-SH cell. Neuroreport 10(1):113–116PubMedGoogle Scholar
  62. 62.
    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(43):40288–40292PubMedGoogle Scholar
  63. 63.
    Kinoshita A, Whelan CM, Berezovska O, Hyman BT (2002) The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. J Biol Chem 277(32):28530–28536PubMedGoogle Scholar
  64. 64.
    Koo EH, Park L, Selkoe DJ (1993) Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. Proc Natl Acad Sci 90(10):4748–4752PubMedCentralPubMedGoogle Scholar
  65. 65.
    Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wullner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J (2011) Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease. EMBO J 30(11):2255–2265PubMedCentralPubMedGoogle Scholar
  66. 66.
    Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, Konig S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT (2011) Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron 71(5):833–844PubMedGoogle Scholar
  67. 67.
    Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27(4):796–807PubMedGoogle Scholar
  68. 68.
    Lalowski M, Golabek A, Lemere CA, Selkoe DJ, Wisniewski HM, Beavis RC, Frangione B, Wisniewski T (1996) The “nonamyloidogenic” p3 fragment (amyloid beta17-42) is a major constituent of Down’s syndrome cerebellar preamyloid. J Biol Chem 271(52):33623–33631PubMedGoogle Scholar
  69. 69.
    Lannfelt L, Basun H, Wahlund LO, Rowe BA, Wagner SL (1995) Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s disease. Nat Med 1(8):829–832PubMedGoogle Scholar
  70. 70.
    LeBlanc A, Liu H, Goodyer C, Bergeron C, Hammond J (1999) Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. J Biol Chem 274(33):23426–23436PubMedGoogle Scholar
  71. 71.
    Lefort R, Pozueta J, Shelanski M (2012) Cross-linking of cell surface amyloid precursor protein leads to increased beta-amyloid peptide production in hippocampal neurons: implications for Alzheimer’s disease. J Neurosci 32(31):10674–10685PubMedCentralPubMedGoogle Scholar
  72. 72.
    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 A beta fragment of Alzheimer’s disease precursor protein in the hippocampus of aged transgenic mice. J Neurochem 72(6):2479–2487PubMedGoogle Scholar
  73. 73.
    Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH, Bredesen DE (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat Med 6(4):397–404PubMedGoogle Scholar
  74. 74.
    Lu DC, Shaked GM, Masliah E, Bredesen DE, Koo EH (2003) Amyloid beta protein toxicity mediated by the formation of amyloid-beta protein precursor complexes. Ann Neurol 54(6):781–789PubMedGoogle Scholar
  75. 75.
    Lu DC, Soriano S, Bredesen DE, Koo EH (2003) Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. J Neurochem 87(3):733–741PubMedGoogle Scholar
  76. 76.
    Madeira A, Pommet JM, Prochiantz A, Allinquant B (2005) SET protein (TAF1beta, I2PP2A) is involved in neuronal apoptosis induced by an amyloid precursor protein cytoplasmic subdomain. FASEB J 19(13):1905–1907PubMedGoogle Scholar
  77. 77.
    Marik SA, Olsen O, Tessier-Lavigne M, Gilbert CD (2013) Death receptor 6 regulates adult experience-dependent cortical plasticity. J Neurosci 33(38):14998–15003PubMedCentralPubMedGoogle Scholar
  78. 78.
    Maruyama K, Kumagae Y, Saito Y, Yamao-Harigaya W, Usami M, Ishiura S, Kawashima S, Obata K (1994) The toxic effect of Alzheimer amyloid protein precursor overexpressed in the neuroblastoma cell line NB-1 on neurite outgrowth. Gerontology 40(Suppl 2):57–64PubMedGoogle Scholar
  79. 79.
    Matrone C (2013) A new molecular explanation for age-related neurodegeneration: the Tyr682 residue of amyloid precursor protein. Bioessays 35(10):847–852PubMedCentralPubMedGoogle Scholar
  80. 80.
    Matrone C, Luvisetto S, La Rosa LR, Tamayev R, Pignataro A, Canu N, Yang L, Barbagallo AP, Biundo F, Lombino F, Zheng H, Ammassari-Teule M, D’Adamio L (2012) Tyr682 in the Abeta-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 11(6):1084–1093PubMedCentralPubMedGoogle Scholar
  81. 81.
    McLoughlin DM, Miller CC (2008) The FE65 proteins and Alzheimer’s disease. J Neurosci Res 86(4):744–754PubMedGoogle Scholar
  82. 82.
    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. Mol Brain Res 97(1):103–113PubMedGoogle Scholar
  83. 83.
    Meziane H, Dodart JC, Mathis C, Little S, Clemens J, Paul SM, Ungerer A (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci 95(21):12683–12688PubMedCentralPubMedGoogle Scholar
  84. 84.
    Midthune B, Maruyama H, Malinow R, Koo EH (2011) Elimination of APP caspase cleavage site D664 attenuates Aβ-mediated synaptic depression. Alzheimer’s Dementia 7(4):S588Google Scholar
  85. 85.
    Mileusnic R, Lancashire CL, Rose SP (2004) The peptide sequence Arg-Glu-Arg, present in the amyloid precursor protein, protects against memory loss caused by A beta and acts as a cognitive enhancer. Eur J Neurosci 19(7):1933–1938PubMedGoogle Scholar
  86. 86.
    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):151–167PubMedGoogle Scholar
  87. 87.
    Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11):4050–4058PubMedGoogle Scholar
  88. 88.
    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(4):393–406PubMedGoogle Scholar
  89. 89.
    Murray MM, Bernstein SL, Nyugen V, Condron MM, Teplow DB, Bowers MT (2009) Amyloid beta protein: abeta40 inhibits Abeta42 oligomerization. J Am Chem Soc 131(18):6316–6317PubMedCentralPubMedGoogle Scholar
  90. 90.
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103PubMedGoogle Scholar
  91. 91.
    Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, Verge G, Momoli F, Welner SA, Massicotte G, Julien JP, Shapiro ML (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387(6632):500–505PubMedGoogle Scholar
  92. 92.
    Neve RL, Boyce FM, McPhie DL, Greenan J, Oster-Granite ML (1996) Transgenic mice expressing APP-C100 in the brain. Neurobiol Aging 17(2):191–203PubMedGoogle Scholar
  93. 93.
    Neve RL, Kammesheidt A, Hohmann CF (1992) Brain transplants of cells expressing the carboxyl-terminal fragment of the Alzheimer amyloid protein precursor cause specific neuropathology in vivo. Proc Natl Acad Sci 89(8):3448–3452PubMedCentralPubMedGoogle Scholar
  94. 94.
    Nhan HS, Midthune B, Zhang C, Tyan SH, Malinow R, Koo EH (2013) Benefits of the APP caspase cleavage site mutation at position D664 include attenuation of Aβ-induced post-synaptic AMPAR/NMDAR-mediated currents and attenuation of Aβ-induced spine loss in knock-in animals. Program No. 429.16. 2013 Neuroscience Meeting Planner, Society for Neuroscience, San Diego. OnlineGoogle Scholar
  95. 95.
    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):981–989PubMedCentralPubMedGoogle Scholar
  96. 96.
    Nishimura I, Uetsuki T, Dani SU, Ohsawa Y, Saito I, Okamura H, Uchiyama Y, Yoshikawa K (1998) Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer. J Neurosci 18(7):2387–2398PubMedGoogle Scholar
  97. 97.
    Olsen O, Kallop DY, McLaughlin T, Huntwork-Rodriguez S, Wu Z, Duggan CD, Simon DJ, Lu Y, Easley-Neal C, Takeda K, Hass PE, Jaworski A, O’Leary DD, Weimer RM, Tessier-Lavigne M (2014) Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of beta-secretase. J Neurosci 34(19):6438–6447PubMedCentralPubMedGoogle Scholar
  98. 98.
    Ozaki T, Li Y, Kikuchi H, Tomita T, Iwatsubo T, Nakagawara A (2006) The intracellular domain of the amyloid precursor protein (AICD) enhances the p53-mediated apoptosis. Biochem Biophys Res Commun 351(1):57–63PubMedGoogle Scholar
  99. 99.
    Park SA, Shaked GM, Bredesen DE, Koo EH (2009) Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein. Biochem Biophys Res Commun 388(2):450–455PubMedCentralPubMedGoogle Scholar
  100. 100.
    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 gamma-secretase cleavage of Alzheimer’s amyloid beta protein precursor. J Alzheimers Dis 2(3–4):289–301PubMedGoogle Scholar
  101. 101.
    Pellegrini L, Passer BJ, Tabaton M, Ganjei JK, D’Adamio L (1999) Alternative, non-secretase processing of Alzheimer’s beta-amyloid precursor protein during apoptosis by caspase-6 and -8. J Biol Chem 274(30):21011–21016PubMedGoogle Scholar
  102. 102.
    Portelius E, Brinkmalm G, Tran A, Andreasson U, Zetterberg H, Westman-Brinkmalm A, Blennow K, Ohrfelt A (2010) Identification of novel N-terminal fragments of amyloid precursor protein in cerebrospinal fluid. Exp Neurol 223(2):351–358PubMedGoogle Scholar
  103. 103.
    Postina R (2008) A closer look at alpha-secretase. Curr Alzheimer Res 5(2):179–186PubMedGoogle Scholar
  104. 104.
    Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC (1998) Molecular mapping of Alzheimer-type dementia in down’s syndrome. Ann Neurol 43(3):380–383PubMedGoogle Scholar
  105. 105.
    Rah JC, Kim HS, Kim SS, Bach JH, Kim YS, Park CH, Seo JH, Jeong SJ, Suh YH (2001) Effects of carboxyl-terminal fragment of Alzheimer’s amyloid precursor protein and amyloid beta-peptide on the production of cytokines and nitric oxide in glial cells. FASEB J 15(8):1463–1465PubMedGoogle Scholar
  106. 106.
    Recuero M, Serrano E, Bullido MJ, Valdivieso F (2004) Abeta production as consequence of cellular death of a human neuroblastoma overexpressing APP. FEBS Lett 570(1–3):114–118PubMedGoogle Scholar
  107. 107.
    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
  108. 108.
    Roch JM, Masliah E, Roch-Levecq AC, Sundsmo MP, Otero DA, Veinbergs I, Saitoh T (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci 91(16):7450–7454PubMedCentralPubMedGoogle Scholar
  109. 109.
    Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW (1999) Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat Struct Biol 6(4):327–331PubMedGoogle Scholar
  110. 110.
    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
  111. 111.
    Rutten BP, Wirths O, Van de Berg WD, Lichtenthaler SF, Vehoff J, Steinbusch HW, Korr H, Beyreuther K, Multhaup G, Bayer TA, Schmitz C (2003) No alterations of hippocampal neuronal number and synaptic bouton number in a transgenic mouse model expressing the beta-cleaved C-terminal APP fragment. Neurobiol Dis 12(2):110–120PubMedGoogle Scholar
  112. 112.
    Ryan KA, Pimplikar SW (2005) Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol 171(2):327–335PubMedCentralPubMedGoogle Scholar
  113. 113.
    Saganich MJ, Schroeder BE, Galvan V, Bredesen DE, Koo EH, Heinemann SF (2006) Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP. J Neurosci 26(52):13428–13436PubMedGoogle Scholar
  114. 114.
    Saitoh T, Sundsmo M, Roch JM, Kimura N, Cole G, Schubert D, Oltersdorf T, Schenk DB (1989) Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell 58(4):615–622PubMedGoogle Scholar
  115. 115.
    Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51(1):29–42PubMedGoogle Scholar
  116. 116.
    Sato M, Kawarabayashi T, Shoji M, Kobayashi T, Tada N, Matsubara E, Hirai S (1997) Neurodegeneration and gliosis in transgenic mice overexpressing a carboxy-terminal fragment of Alzheimer amyloid-beta protein precursor. Dement Geriatr Cogn Disord 8(5):296–307PubMedGoogle Scholar
  117. 117.
    Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y (2003) Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49–99 of beta-amyloid precursor protein. J Biol Chem 278(27):24294–24301PubMedGoogle Scholar
  118. 118.
    Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Bohm G, Demuth HU (2006) On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry 45(41):12393–12399PubMedGoogle Scholar
  119. 119.
    Schubert D, Behl C (1993) The expression of amyloid beta protein precursor protects nerve cells from beta-amyloid and glutamate toxicity and alters their interaction with the extracellular matrix. Brain Res 629(2):275–282PubMedGoogle Scholar
  120. 120.
    Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875PubMedGoogle Scholar
  121. 121.
    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842PubMedCentralPubMedGoogle Scholar
  122. 122.
    Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402(6761):537–540PubMedGoogle Scholar
  123. 123.
    Small DH, Nurcombe V, Reed G, Clarris H, Moir R, Beyreuther K, Masters CL (1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer’s disease is involved in the regulation of neurite outgrowth. J Neurosci 14(4):2117–2127PubMedGoogle Scholar
  124. 124.
    Smith-Swintosky VL, Pettigrew LC, Craddock SD, Culwell AR, Rydel RE, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63(2):781–784PubMedGoogle Scholar
  125. 125.
    Song DK, Won MH, Jung JS, Lee JC, Kang TC, Suh HW, Huh SO, Paek SH, Kim YH, Kim SH, Suh YH (1998) Behavioral and neuropathologic changes induced by central injection of carboxyl-terminal fragment of beta-amyloid precursor protein in mice. J Neurochem 71(2):875–878PubMedGoogle Scholar
  126. 126.
    Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82(4):756–771PubMedGoogle Scholar
  127. 127.
    Strazielle C, Dumont M, Fukuchi K, Lalonde R (2004) Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on cytochrome oxidase activity in skeletal muscle and brain. J Chem Neuroanat 27(4):237–246PubMedGoogle Scholar
  128. 128.
    Szczepanik AM, Rampe D, Ringheim GE (2001) Amyloid-beta peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo. J Neurochem 77(1):304–317PubMedGoogle Scholar
  129. 129.
    Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J, Urano T, Sakaki Y, Shirahige K, Sasano H, Takahashi S, Kitamura T, Ouchi Y, Aburatani H, Inoue S (2009) Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 69(1):137–142PubMedGoogle Scholar
  130. 130.
    Tampellini D, Capetillo-Zarate E, Dumont M, Huang Z, Yu F, Lin MT, Gouras GK (2010) Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer’s disease transgenic mice. J Neurosci 30(43):14299–14304PubMedCentralPubMedGoogle Scholar
  131. 131.
    Taylor CJ, Ireland DR, Ballagh I, Bourne K, Marechal NM, Turner PR, Bilkey DK, Tate WP, Abraham WC (2008) Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol Dis 31(2):250–260PubMedGoogle Scholar
  132. 132.
    Thal DR, Capetillo-Zarate E, Schultz C, Rub U, Saido TC, Yamaguchi H, Haass C, Griffin WS, Del Tredici K, Braak H, Ghebremedhin E (2005) Apolipoprotein E co-localizes with newly formed amyloid beta-protein (Abeta) deposits lacking immunoreactivity against N-terminal epitopes of Abeta in a genotype-dependent manner. Acta Neuropathol 110(5):459–471PubMedGoogle Scholar
  133. 133.
    Thornton E, Vink R, Blumbergs PC, Van Den Heuvel C (2006) Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res 1094(1):38–46PubMedGoogle Scholar
  134. 134.
    Troy CM, Rabacchi SA, Friedman WJ, Frappier TF, Brown K, Shelanski ML (2000) Caspase-2 mediates neuronal cell death induced by beta-amyloid. J Neurosci 20(4):1386–1392PubMedGoogle Scholar
  135. 135.
    Uetsuki T, Takemoto K, Nishimura I, Okamoto M, Niinobe M, Momoi T, Miura M, Yoshikawa K (1999) Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. J Neurosci 19(16):6955–6964PubMedGoogle Scholar
  136. 136.
    Vella LJ, Cappai R (2012) Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments. FASEB J 26(7):2930–2940PubMedGoogle Scholar
  137. 137.
    Vogt DL, Thomas D, Galvan V, Bredesen DE, Lamb BT, Pimplikar SW (2011) Abnormal neuronal networks and seizure susceptibility in mice overexpressing the APP intracellular domain. Neurobiol Aging 32(9):1725–1729PubMedGoogle Scholar
  138. 138.
    Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101(5):1172–1184PubMedGoogle Scholar
  139. 139.
    Wei W, Norton DD, Wang X, Kusiak JW (2002) Abeta 17–42 in Alzheimer’s disease activates JNK and caspase-8 leading to neuronal apoptosis. Brain 125(Pt 9):2036–2043PubMedGoogle Scholar
  140. 140.
    Weidemann A, Paliga K, Durrwang U, Reinhard FB, Schuckert O, Evin G, Masters CL (1999) Proteolytic processing of the Alzheimer’s disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. J Biol Chem 274(9):5823–5829PubMedGoogle Scholar
  141. 141.
    Whitson JS, Selkoe DJ, Cotman CW (1989) Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243(4897):1488–1490PubMedGoogle Scholar
  142. 142.
    Wolfe MS (2009) gamma-Secretase in biology and medicine. Semin Cell Dev Biol 20(2):219–224PubMedGoogle Scholar
  143. 143.
    Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245(4916):417–420PubMedGoogle Scholar
  144. 144.
    Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250(4978):279–282PubMedGoogle Scholar
  145. 145.
    Yoshikawa K, Aizawa T, Hayashi Y (1992) Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359(6390):64–67PubMedGoogle Scholar
  146. 146.
    Zheng H, Koo EH (2011) Biology and pathophysiology of the amyloid precursor protein. Mol Neurodegener 6(1):27PubMedCentralPubMedGoogle Scholar
  147. 147.
    Zhou ZD, Chan CH, Ma QH, Xu XH, Xiao ZC, Tan EK (2011) The roles of amyloid precursor protein (APP) in neurogenesis: implications to pathogenesis and therapy of Alzheimer disease. Cell Adhes Migr 5(4):280–292Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  2. 2.Departments of Medicine and PhysiologyYong Loo Lin School of Medicine, National University of SingaporeSingaporeSingapore

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