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Cellular Trafficking of Amyloid Precursor Protein in Amyloidogenesis Physiological and Pathological Significance

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Abstract

The accumulation of excess intracellular or extracellular amyloid beta (Aβ) is one of the key pathological events in Alzheimer’s disease (AD). Aβ is generated from the cleavage of amyloid precursor protein (APP) by beta secretase-1 (BACE1) and gamma secretase (γ-secretase) within the cells. The endocytic trafficking of APP facilitates amyloidogenesis while at the cell surface, APP is predominantly processed in a non-amyloidogenic manner. Several adaptor proteins bind to both APP and BACE1, regulating their trafficking and recycling along the secretory and endocytic pathways. The phosphorylation of APP at Thr668 and BACE1 at Ser498, also influence their trafficking. Neurotrophins and proneurotrophins also influence APP trafficking through their receptors. In this review, we describe the molecular trafficking pathways of APP and BACE1 that lead to Aβ generation, the involvement of different signaling molecules or adaptor proteins regulating APP and BACE1 subcellular localization. We have also discussed how neurotrophins could modulate amyloidogenesis through their receptors.

Keywords

APP BACE1 Cellular trafficking Gamma-secretase Amyloidogenesis 

Notes

Acknowledgements

This work was supported by NHMRC grants (XFZ&YJW) and University President’s Scholarship (NBM).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12(4):459–509Google Scholar
  2. 2.
    Naj AC, Schellenberg GD, Alzheimer’s Disease Genetics Consortium (2017) Genomic variants, genes, and pathways of Alzheimer’s disease: an overview. Am J Med Genet B Neuropsychiatr Genet 174(1):5–26.  https://doi.org/10.1002/ajmg.b.32499 PubMedGoogle Scholar
  3. 3.
    Martin P, Comas-Herrera, A., Knapp, M., Guerchet, M., Karagiannidou, M. (2016) World Alzheimer report 2016: improving healthcare for people living with dementia. Alzheimer’s Disease InternationalGoogle Scholar
  4. 4.
    Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 425(3):534–539.  https://doi.org/10.1016/j.bbrc.2012.08.020 Google Scholar
  5. 5.
    Glenner GG, Wong CW, Quaranta V, Eanes ED (1984) The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol 2(6):357–369PubMedGoogle Scholar
  6. 6.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  7. 7.
    Ubhi K, Masliah E (2013) Alzheimer’s disease: recent advances and future perspectives. J Alzheimers Dis: JAD 33(Suppl 1):S185–S194.  https://doi.org/10.3233/JAD-2012-129028 PubMedGoogle Scholar
  8. 8.
    Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587(13):2046–2054.  https://doi.org/10.1016/j.febslet.2013.05.010 PubMedGoogle Scholar
  9. 9.
    Saadipour K, Manucat-Tan NB, Lim Y, Keating DJ, Smith KS, Zhong JH, Liao H, Bobrovskaya L et al (2017) p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. J Neurochem.  https://doi.org/10.1111/jnc.14206
  10. 10.
    Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120(4):545–555.  https://doi.org/10.1016/j.cell.2005.02.008 PubMedGoogle Scholar
  11. 11.
    Cappai R, White AR (1999) Amyloid beta. Int J Biochem Cell Biol 31(9):885–889PubMedGoogle Scholar
  12. 12.
    Bursavich MG, Harrison BA, Blain JF (2016) Gamma secretase modulators: new Alzheimer’s drugs on the horizon? J Med Chem 59(16):7389–7409.  https://doi.org/10.1021/acs.jmedchem.5b01960 PubMedGoogle Scholar
  13. 13.
    Selkoe DJ (2004) Cell biology of protein misfolding: The examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6(11):1054–1061.  https://doi.org/10.1038/ncb1104-1054 PubMedGoogle Scholar
  14. 14.
    LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509.  https://doi.org/10.1038/nrn2168 PubMedGoogle Scholar
  15. 15.
    Dawkins E, Small DH (2014) Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem 129(5):756–769.  https://doi.org/10.1111/jnc.12675 PubMedPubMedCentralGoogle Scholar
  16. 16.
    Belyaev ND, Kellett KA, Beckett C, Makova NZ, Revett TJ, Nalivaeva NN, Hooper NM, Turner AJ (2010) The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. J Biol Chem 285(53):41443–41454.  https://doi.org/10.1074/jbc.M110.141390 PubMedPubMedCentralGoogle Scholar
  17. 17.
    Kirazov E, Kirazov L, Bigl V, Schliebs R (2001) Ontogenetic changes in protein level of amyloid precursor protein (APP) in growth cones and synaptosomes from rat brain and prenatal expression pattern of APP mRNA isoforms in developing rat embryo. Int J Dev Neurosci 19(3):287–296PubMedGoogle Scholar
  18. 18.
    Akaaboune M, Allinquant B, Farza H, Roy K, Magoul R, Fiszman M, Festoff BW, Hantai D (2000) Developmental regulation of amyloid precursor protein at the neuromuscular junction in mouse skeletal muscle. Mol Cell Neurosci 15(4):355–367PubMedGoogle Scholar
  19. 19.
    Zou C, Crux S, Marinesco S, Montagna E, Sgobio C, Shi Y, Shi S, Zhu K et al (2016) Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D-serine homeostasis. EMBO J 35(20):2213–2222.  https://doi.org/10.15252/embj.201694085 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hoe HS, Lee HK, Pak DT (2012) The upside of APP at synapses. CNS Neurosci Ther 18(1):47–56.  https://doi.org/10.1111/j.1755-5949.2010.00221.x PubMedGoogle Scholar
  21. 21.
    Pandey P, Sliker B, Peters HL, Tuli A, Herskovitz J, Smits K, Purohit A, Singh RK et al (2016) Amyloid precursor protein and amyloid precursor-like protein 2 in cancer. Oncotarget 7(15):19430–19444.  https://doi.org/10.18632/oncotarget.7103 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2(5):a006270.  https://doi.org/10.1101/cshperspect.a006270 PubMedPubMedCentralGoogle Scholar
  23. 23.
    Vassar R (2004) BACE1: The beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci: MN 23(1–2):105–114.  https://doi.org/10.1385/JMN:23:1-2:105 PubMedGoogle Scholar
  24. 24.
    Wahle T, Prager K, Raffler N, Haass C, Famulok M, Walter J (2005) GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. Mol Cell Neurosci 29(3):453–461.  https://doi.org/10.1016/j.mcn.2005.03.014 PubMedGoogle Scholar
  25. 25.
    Evin G, Barakat A, Masters CL (2010) BACE: therapeutic target and potential biomarker for Alzheimer’s disease. Int J Biochem Cell Biol 42(12):1923–1926.  https://doi.org/10.1016/j.biocel.2010.08.017 PubMedGoogle Scholar
  26. 26.
    Kandalepas PC, Vassar R (2014) The normal and pathologic roles of the Alzheimer’s beta-secretase, BACE1. Curr Alzheimer Res 11(5):441–449PubMedPubMedCentralGoogle Scholar
  27. 27.
    Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, Lammich S, Multhaup G et al (2000) Maturation and pro-peptide cleavage of beta-secretase. J Biol Chem 275(40):30849–30854.  https://doi.org/10.1074/jbc.M003202200 PubMedGoogle Scholar
  28. 28.
    Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283(44):29615–29619.  https://doi.org/10.1074/jbc.R800019200 PubMedPubMedCentralGoogle Scholar
  29. 29.
    Zhang X, Song W (2013) The role of APP and BACE1 trafficking in APP processing and amyloid-beta generation. Alzheimers Res Ther 5(5):46.  https://doi.org/10.1186/alzrt211 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Arbor S (2017) Targeting amyloid precursor protein shuttling and processing—long before amyloid beta formation. Neural Regen Res 12(2):207–209.  https://doi.org/10.4103/1673-5374.200800 PubMedPubMedCentralGoogle Scholar
  31. 31.
    Cole SL, Vassar R (2007) The basic biology of BACE1: a key therapeutic target for Alzheimer’s disease. Curr Genomics 8(8):509–530.  https://doi.org/10.2174/138920207783769512 PubMedPubMedCentralGoogle Scholar
  32. 32.
    Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH et al (2007) Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 54(5):721–737.  https://doi.org/10.1016/j.neuron.2007.05.012 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Chia PZ, Gleeson PA (2011) Intracellular trafficking of the beta-secretase and processing of amyloid precursor protein. IUBMB Life 63(9):721–729.  https://doi.org/10.1002/iub.512 PubMedGoogle Scholar
  34. 34.
    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):393–406.  https://doi.org/10.1016/j.pneurobio.2008.05.002 PubMedGoogle Scholar
  35. 35.
    Tam JH, Cobb MR, Seah C, Pasternak SH (2016) Tyrosine binding protein sites regulate the intracellular trafficking and processing of amyloid precursor protein through a novel lysosome-directed pathway. PLoS One 11(10):e0161445.  https://doi.org/10.1371/journal.pone.0161445 PubMedPubMedCentralGoogle Scholar
  36. 36.
    Poulsen ET, Larsen A, Zollo A, Jorgensen AL, Sanggaard KW, Enghild JJ, Matrone C (2015) New insights to clathrin and adaptor protein 2 for the design and development of therapeutic strategies. Int J Mol Sci 16(12):29446–29453.  https://doi.org/10.3390/ijms161226181 PubMedPubMedCentralGoogle Scholar
  37. 37.
    Lee J, Retamal C, Cuitino L, Caruano-Yzermans A, Shin JE, van Kerkhof P, Marzolo MP, Bu G (2008) Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes. J Biol Chem 283(17):11501–11508.  https://doi.org/10.1074/jbc.M800642200 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Toh WH, Tan JZ, Zulkefli KL, Houghton FJ, Gleeson PA (2017) Amyloid precursor protein traffics from the Golgi directly to early endosomes in an Arl5b- and AP4-dependent pathway. Traffic 18(3):159–175.  https://doi.org/10.1111/tra.12465 PubMedGoogle Scholar
  39. 39.
    Icking A, Amaddii M, Ruonala M, Honing S, Tikkanen R (2007) Polarized transport of Alzheimer amyloid precursor protein is mediated by adaptor protein complex AP1-1B. Traffic 8(3):285–296.  https://doi.org/10.1111/j.1600-0854.2006.00526.x PubMedGoogle Scholar
  40. 40.
    Sakurai T, Kaneko K, Okuno M, Wada K, Kashiyama T, Shimizu H, Akagi T, Hashikawa T et al (2008) Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing. J Cell Biol 183(2):339–352.  https://doi.org/10.1083/jcb.200804075 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Kondo M, Shiono M, Itoh G, Takei N, Matsushima T, Maeda M, Taru H, Hata S et al (2010) Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain. Mol Neurodegener 5:35.  https://doi.org/10.1186/1750-1326-5-35 PubMedPubMedCentralGoogle Scholar
  42. 42.
    Shrivastava-Ranjan P, Faundez V, Fang G, Rees H, Lah JJ, Levey AI, Kahn RA (2008) Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer’s precursor protein from the trans-Golgi network. Mol Biol Cell 19(1):51–64.  https://doi.org/10.1091/mbc.E07-05-0465 PubMedPubMedCentralGoogle Scholar
  43. 43.
    Yang M, Virassamy B, Vijayaraj SL, Lim Y, Saadipour K, Wang YJ, Han YC, Zhong JH et al (2013) The intracellular domain of sortilin interacts with amyloid precursor protein and regulates its lysosomal and lipid raft trafficking. PLoS One 8(5):e63049.  https://doi.org/10.1371/journal.pone.0063049 PubMedPubMedCentralGoogle Scholar
  44. 44.
    King GD, Perez RG, Steinhilb ML, Gaut JR, Turner RS (2003) X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence. Neuroscience 120(1):143–154PubMedGoogle Scholar
  45. 45.
    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 16Google Scholar
  46. 46.
    Lee JH, Lau KF, Perkinton MS, Standen CL, Rogelj B, Falinska A, McLoughlin DM, Miller CC (2004) The neuronal adaptor protein X11beta reduces amyloid beta-protein levels and amyloid plaque formation in the brains of transgenic mice. J Biol Chem 279(47):49099–49104.  https://doi.org/10.1074/jbc.M405602200 PubMedGoogle Scholar
  47. 47.
    Weyer SW, Klevanski M, Delekate A, Voikar V, Aydin D, Hick M, Filippov M, Drost N et al (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30(11):2266–2280.  https://doi.org/10.1038/emboj.2011.119 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Shin YK (2013) Two gigs of Munc18 in membrane fusion. Proc Natl Acad Sci U S A 110(35):14116–14117.  https://doi.org/10.1073/pnas.1313749110 PubMedPubMedCentralGoogle Scholar
  49. 49.
    Schettini G, Govoni S, Racchi M, Rodriguez G (2010) Phosphorylation of APP-CTF-AICD domains and interaction with adaptor proteins: signal transduction and/or transcriptional role—relevance for Alzheimer pathology. J Neurochem 115(6):1299–1308.  https://doi.org/10.1111/j.1471-4159.2010.07044.x PubMedGoogle Scholar
  50. 50.
    Lichtenthaler SF (2006) Ectodomain shedding of the amyloid precursor protein: cellular control mechanisms and novel modifiers. Neurodegener Dis 3(4–5):262–269.  https://doi.org/10.1159/000095265 PubMedGoogle Scholar
  51. 51.
    Chaufty J, Sullivan SE, Ho A (2012) Intracellular amyloid precursor protein sorting and amyloid-beta secretion are regulated by Src-mediated phosphorylation of Mint2. J Neurosci: Off J Soc Neurosci 32(28):9613–9625.  https://doi.org/10.1523/JNEUROSCI.0602-12.2012 Google Scholar
  52. 52.
    He X, Cooley K, Chung CH, Dashti N, Tang J (2007) Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci: Off J Soc Neurosci 27(15):4052–4060.  https://doi.org/10.1523/JNEUROSCI.3993-06.2007 Google Scholar
  53. 53.
    Cao X, Sudhof TC (2004) Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation. J Biol Chem 279(23):24601–24611.  https://doi.org/10.1074/jbc.M402248200 PubMedGoogle Scholar
  54. 54.
    Fiore F, Zambrano N, Minopoli G, Donini V, Duilio A, Russo T (1995) The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer’s amyloid precursor protein. J Biol Chem 270Google Scholar
  55. 55.
    Borquez DA, Gonzalez-Billault C (2012) The amyloid precursor protein intracellular domain-fe65 multiprotein complexes: a challenge to the amyloid hypothesis for Alzheimer’s disease? Int J Alzheimers Dis 2012:353145.  https://doi.org/10.1155/2012/353145 PubMedPubMedCentralGoogle Scholar
  56. 56.
    Xu X, Zhou H, Boyer TG (2011) Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling. EMBO Rep 12(3):216–222.  https://doi.org/10.1038/embor.2010.210 PubMedPubMedCentralGoogle Scholar
  57. 57.
    Feilen LP, Haubrich K, Strecker P, Probst S, Eggert S, Stier G, Sinning I, Konietzko U et al (2017) Fe65-PTB2 dimerization mimics Fe65-APP interaction. Front Mol Neurosci 10:140.  https://doi.org/10.3389/fnmol.2017.00140 PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cao X, Sudhof TC (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293(5527):115–120.  https://doi.org/10.1126/science.1058783 PubMedGoogle Scholar
  59. 59.
    Pardossi-Piquard R, Checler F (2012) The physiology of the beta-amyloid precursor protein intracellular domain AICD. J Neurochem 120(Suppl 1):109–124.  https://doi.org/10.1111/j.1471-4159.2011.07475.x PubMedGoogle Scholar
  60. 60.
    Chang KA, Kim HS, Ha TY, Ha JW, Shin KY, Jeong YH, Lee JP, Park CH et al (2006) Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol 26(11):4327–4338.  https://doi.org/10.1128/MCB.02393-05 PubMedPubMedCentralGoogle Scholar
  61. 61.
    Barbato C, Canu N, Zambrano N, Serafino A, Minopoli G, Ciotti MT, Amadoro G, Russo T et al (2005) Interaction of tau with Fe65 links tau to APP. Neurobiol Dis 18(2):399–408.  https://doi.org/10.1016/j.nbd.2004.10.011 PubMedGoogle Scholar
  62. 62.
    Trommsdorff M, Borg JP, Margolis B, Herz J (1998) Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem 273(50):33556–33560PubMedGoogle Scholar
  63. 63.
    Jiang S, Li Y, Zhang X, Bu G, Xu H, Zhang YW (2014) Trafficking regulation of proteins in Alzheimer’s disease. Mol Neurodegener 9:6.  https://doi.org/10.1186/1750-1326-9-6 PubMedPubMedCentralGoogle Scholar
  64. 64.
    Ulery PG, Beers J, Mikhailenko I, Tanzi RE, Rebeck GW, Hyman BT, Strickland DK (2000) Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer’s disease. J Biol Chem 275(10):7410–7415PubMedGoogle Scholar
  65. 65.
    Pietrzik CU, Yoon IS, Jaeger S, Busse T, Weggen S, Koo EH (2004) FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein. J Neurosci: Off J Soc Neurosci 24(17):4259–4265.  https://doi.org/10.1523/JNEUROSCI.5451-03.2004 Google Scholar
  66. 66.
    Cam JA, Zerbinatti CV, Knisely JM, Hecimovic S, Li Y, Bu G (2004) The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. The Journal of Biological Chemistry 279Google Scholar
  67. 67.
    Pohlkamp T, Wasser CR, Herz J (2017) Functional roles of the interaction of APP and lipoprotein receptors. Front Mol Neurosci 10:54.  https://doi.org/10.3389/fnmol.2017.00054 PubMedPubMedCentralGoogle Scholar
  68. 68.
    Brodeur J, Theriault C, Lessard-Beaudoin M, Marcil A, Dahan S, Lavoie C (2012) LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease. Mol Neurodegener 7:31.  https://doi.org/10.1186/1750-1326-7-31 PubMedPubMedCentralGoogle Scholar
  69. 69.
    Hoe HS, Tran TS, Matsuoka Y, Howell BW, Rebeck GW (2006) DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J Biol Chem 281(46):35176–35185.  https://doi.org/10.1074/jbc.M602162200 PubMedGoogle Scholar
  70. 70.
    Kwon OY, Hwang K, Kim JA, Kim K, Kwon IC, Song HK, Jeon H (2010) Dab1 binds to Fe65 and diminishes the effect of Fe65 or LRP1 on APP processing. J Cell Biochem 111(2):508–519.  https://doi.org/10.1002/jcb.22738 PubMedGoogle Scholar
  71. 71.
    Taru H, Kirino Y, Suzuki T (2002) Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism. J Biol Chem 277(30):27567–27574.  https://doi.org/10.1074/jbc.M203713200 PubMedGoogle Scholar
  72. 72.
    Chiba K, Araseki M, Nozawa K, Furukori K, Araki Y, Matsushima T, Nakaya T, Hata S et al (2014) Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport. Mol Biol Cell 25(22):3569–3580.  https://doi.org/10.1091/mbc.E14-06-1111 PubMedPubMedCentralGoogle Scholar
  73. 73.
    Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America 102Google Scholar
  74. 74.
    Nielsen MS, Gustafsen C, Madsen P, Nyengaard JR, Hermey G, Bakke O, Mari M, Schu P et al (2007) Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA. Mol Cell Biol 27(19):6842–6851.  https://doi.org/10.1128/MCB.00815-07 PubMedPubMedCentralGoogle Scholar
  75. 75.
    Gustafsen C, Glerup S, Pallesen LT, Olsen D, Andersen OM, Nykjaer A, Madsen P, Petersen CM (2013) Sortilin and SorLA display distinct roles in processing and trafficking of amyloid precursor protein. J Neurosci: Off J Soc Neurosci 33(1):64–71.  https://doi.org/10.1523/JNEUROSCI.2371-12.2013 Google Scholar
  76. 76.
    Ruan CS, Yang CR, Li JY, Luo HY, Bobrovskaya L, Zhou XF (2016) Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior. Exp Neurol 281:99–108.  https://doi.org/10.1016/j.expneurol.2016.04.015 PubMedGoogle Scholar
  77. 77.
    Hu X, Hu ZL, Li Z, Ruan CS, Qiu WY, Pan A, Li CQ, Cai Y, Shen L, Chu Y, Tang BS, Cai H, Zhou XF, Ma C, Yan XX (2017) Sortilin fragments deposit at senile plaques in human cerebrum. Front Neuroanat 11:45. doi: https://doi.org/10.3389/fnana.2017.00045
  78. 78.
    Finan GM, Okada H, Kim TW (2011) BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. J Biol Chem 286(14):12602–12616.  https://doi.org/10.1074/jbc.M110.170217 PubMedPubMedCentralGoogle Scholar
  79. 79.
    Ruan CS, Liu J, Yang M, Saadipour K, Zeng YQ, Liao H, Wang YJ, Bobrovskaya L et al (2018) Sortilin inhibits amyloid pathology by regulating non-specific degradation of APP. Experimental Neurology 299(Pt a):75–85.  https://doi.org/10.1016/j.expneurol.2017.10.018 PubMedGoogle Scholar
  80. 80.
    Saadipour K, Yang M, Lim Y, Georgiou K, Sun Y, Keating D, Liu J, Wang YR et al (2013) Amyloid beta(1)(−)(4)(2) (Abeta(4)(2)) up-regulates the expression of sortilin via the p75(NTR)/RhoA signaling pathway. J Neurochem 127(2):152–162.  https://doi.org/10.1111/jnc.12383 PubMedGoogle Scholar
  81. 81.
    Mufson EJ, Wuu J, Counts SE, Nykjaer A (2010) Preservation of cortical sortilin protein levels in MCI and Alzheimer’s disease. Neurosci Lett 471(3):129–133.  https://doi.org/10.1016/j.neulet.2010.01.023 PubMedPubMedCentralGoogle Scholar
  82. 82.
    Schobel S, Neumann S, Hertweck M, Dislich B, Kuhn PH, Kremmer E, Seed B, Baumeister R et al (2008) A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein. J Biol Chem 283(21):14257–14268.  https://doi.org/10.1074/jbc.M801531200 PubMedGoogle Scholar
  83. 83.
    Ghai R, Bugarcic A, Liu H, Norwood SJ, Skeldal S, Coulson EJ, Li SS, Teasdale RD et al (2013) Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins. Proc Natl Acad Sci U S A 110(8):E643–E652.  https://doi.org/10.1073/pnas.1216229110 PubMedPubMedCentralGoogle Scholar
  84. 84.
    Park JH, Gimbel DA, GrandPre T, Lee JK, Kim JE, Li W, Lee DH, Strittmatter SM (2006) Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition. J Neurosci: Off J Soc Neurosci 26(5):1386–1395.  https://doi.org/10.1523/JNEUROSCI.3291-05.2006 Google Scholar
  85. 85.
    Tam JH, Seah C, Pasternak SH (2014) The amyloid precursor protein is rapidly transported from the Golgi apparatus to the lysosome and where it is processed into beta-amyloid. Mol Brain 7:54.  https://doi.org/10.1186/s13041-014-0054-1 PubMedPubMedCentralGoogle Scholar
  86. 86.
    Burgos PV, Mardones GA, Rojas AL, daSilva LL, Prabhu Y, Hurley JH, Bonifacino JS (2010) Sorting of the Alzheimer’s disease amyloid precursor protein mediated by the AP-4 complex. Dev Cell 18(3):425–436.  https://doi.org/10.1016/j.devcel.2010.01.015 PubMedPubMedCentralGoogle Scholar
  87. 87.
    Cam JA, Zerbinatti CV, Knisely JM, Hecimovic S, Li Y, Bu G (2004) The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. J Biol Chem 279(28):29639–29646.  https://doi.org/10.1074/jbc.M313893200 PubMedGoogle Scholar
  88. 88.
    Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T et al (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102(38):13461–13466.  https://doi.org/10.1073/pnas.0503689102 PubMedPubMedCentralGoogle Scholar
  89. 89.
    Hasebe N, Fujita Y, Ueno M, Yoshimura K, Fujino Y, Yamashita T (2013) Soluble beta-amyloid precursor protein alpha binds to p75 neurotrophin receptor to promote neurite outgrowth. PLoS One 8(12):e82321.  https://doi.org/10.1371/journal.pone.0082321 PubMedPubMedCentralGoogle Scholar
  90. 90.
    Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci: Off J Soc Neurosci 28(15):3941–3946.  https://doi.org/10.1523/JNEUROSCI.0350-08.2008 Google Scholar
  91. 91.
    Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100(9):2333–2340.  https://doi.org/10.1172/JCI119772 PubMedPubMedCentralGoogle Scholar
  92. 92.
    Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA (2002) Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem 277(10):7720–7725.  https://doi.org/10.1074/jbc.M110929200 PubMedGoogle Scholar
  93. 93.
    Knowles JK, Rajadas J, Nguyen TV, Yang T, LeMieux MC, Vander Griend L, Ishikawa C, Massa SM et al (2009) The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci 29(34):10627–10637.  https://doi.org/10.1523/JNEUROSCI.0620-09.2009 PubMedPubMedCentralGoogle Scholar
  94. 94.
    Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J et al (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440(7083):528–534.  https://doi.org/10.1038/nature04543 PubMedGoogle Scholar
  95. 95.
    Tamayev R, Zhou D, D’Adamio L (2009) The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener 4:28.  https://doi.org/10.1186/1750-1326-4-28 PubMedPubMedCentralGoogle Scholar
  96. 96.
    Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, Veerle B, Coen K et al (2011) ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A 108(34):E559–E568.  https://doi.org/10.1073/pnas.1100745108 PubMedPubMedCentralGoogle Scholar
  97. 97.
    Prabhu Y, Burgos PV, Schindler C, Farias GG, Magadan JG, Bonifacino JS (2012) Adaptor protein 2-mediated endocytosis of the beta-secretase BACE1 is dispensable for amyloid precursor protein processing. Mol Biol Cell 23(12):2339–2351.  https://doi.org/10.1091/mbc.E11-11-0944 PubMedPubMedCentralGoogle Scholar
  98. 98.
    Walter J (2006) Control of amyloid-beta-peptide generation by subcellular trafficking of the beta-amyloid precursor protein and beta-secretase. Neurodegener Dis 3(4–5):247–254.  https://doi.org/10.1159/000095263 PubMedGoogle Scholar
  99. 99.
    von Einem B, Wahler A, Schips T, Serrano-Pozo A, Proepper C, Boeckers TM, Rueck A, Wirth T et al (2015) The Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins Alter amyloid-beta precursor protein (APP) processing through interaction of their GAE domain with the Beta-site APP cleaving enzyme 1 (BACE1). PLoS One 10(6):e0129047.  https://doi.org/10.1371/journal.pone.0129047 Google Scholar
  100. 100.
    Herskowitz JH, Offe K, Deshpande A, Kahn RA, Levey AI, Lah JJ (2012) GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-beta production. Mol Biol Cell 23(14):2645–2657.  https://doi.org/10.1091/mbc.E12-01-0014 PubMedPubMedCentralGoogle Scholar
  101. 101.
    Kim NY, Cho MH, Won SH, Kang HJ, Yoon SY, Kim DH (2017) Sorting nexin-4 regulates beta-amyloid production by modulating beta-site-activating cleavage enzyme-1. Alzheimers Res Ther 9(1):4.  https://doi.org/10.1186/s13195-016-0232-8 PubMedPubMedCentralGoogle Scholar
  102. 102.
    Toh WH, Chia PZC, Hossain MI, Gleeson PA (2018) GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Abeta production. Mol Biol Cell 29(2):191–208.  https://doi.org/10.1091/mbc.E17-05-0270 PubMedPubMedCentralGoogle Scholar
  103. 103.
    Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW (2010) Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J 24(8):2783–2794.  https://doi.org/10.1096/fj.09-146357 PubMedPubMedCentralGoogle Scholar
  104. 104.
    Zhao Y, Wang Y, Yang J, Wang X, Zhao Y, Zhang X, Zhang YW (2012) Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Mol Neurodegener 7:30.  https://doi.org/10.1186/1750-1326-7-30 PubMedPubMedCentralGoogle Scholar
  105. 105.
    He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R (2004) Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med 10 (9):959–965. doi: https://doi.org/10.1038/nm1088
  106. 106.
    Vassar R, Kovacs DM, Yan R, Wong PC (2009) The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29(41):12787–12794.  https://doi.org/10.1523/JNEUROSCI.3657-09.2009 PubMedPubMedCentralGoogle Scholar
  107. 107.
    Wen L, Tang FL, Hong Y, Luo SW, Wang CL, He W, Shen C, Jung JU et al (2011) VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol 195(5):765–779.  https://doi.org/10.1083/jcb.201105109 PubMedPubMedCentralGoogle Scholar
  108. 108.
    Rajendran L, Annaert W (2012) Membrane trafficking pathways in Alzheimer’s disease. Traffic 13(6):759–770.  https://doi.org/10.1111/j.1600-0854.2012.01332.x PubMedGoogle Scholar
  109. 109.
    Zhao Y, Wang Y, Hu J, Zhang X, Zhang YW (2012) CutA divalent cation tolerance homolog (Escherichia coli) (CUTA) regulates beta-cleavage of beta-amyloid precursor protein (APP) through interacting with beta-site APP cleaving protein 1 (BACE1). J Biol Chem 287(14):11141–11150.  https://doi.org/10.1074/jbc.M111.330209 PubMedPubMedCentralGoogle Scholar
  110. 110.
    Ramelot TA, Nicholson LK (2001) Phosphorylation-induced structural changes in the amyloid precursor protein cytoplasmic tail detected by NMR. J Mol Biol 307(3):871–884.  https://doi.org/10.1006/jmbi.2001.4535 PubMedGoogle Scholar
  111. 111.
    Herskowitz JH, Feng Y, Mattheyses AL, Hales CM, Higginbotham LA, Duong DM, Montine TJ, Troncoso JC et al (2013) Pharmacologic inhibition of ROCK2 suppresses amyloid-beta production in an Alzheimer’s disease mouse model. J Neurosci: Off J Soc Neurosci 33(49):19086–19098.  https://doi.org/10.1523/JNEUROSCI.2508-13.2013 Google Scholar
  112. 112.
    Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, Neve R, Ahlijanian MK, Tsai LH (2003) APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 163 (1):83–95. doi: https://doi.org/10.1083/jcb.200301115
  113. 113.
    Walter J, Fluhrer R, Hartung B, Willem M, Kaether C, Capell A, Lammich S, Multhaup G et al (2001) Phosphorylation regulates intracellular trafficking of beta-secretase. J Biol Chem 276(18):14634–14641.  https://doi.org/10.1074/jbc.M011116200 PubMedGoogle Scholar
  114. 114.
    Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276(16):12660–12666.  https://doi.org/10.1074/jbc.M008104200 PubMedGoogle Scholar
  115. 115.
    Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond Ser B Biol Sci 361(1473):1545–1564.  https://doi.org/10.1098/rstb.2006.1894 Google Scholar
  116. 116.
    Zhou XF (2016) The imbalance of neurotrophic signalling: an alternate hypothesis for the pathogenesis and drug development of Alzheimer’s disease. Proc Neurosci 1(1):13–18Google Scholar
  117. 117.
    Oliveira SL, Pillat MM, Cheffer A, Lameu C, Schwindt TT, Ulrich H (2013) Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry A 83(1):76–89.  https://doi.org/10.1002/cyto.a.22161 PubMedGoogle Scholar
  118. 118.
    Schindowski K, Belarbi K, Buee L (2008) Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes Brain Behav 7(Suppl 1):43–56.  https://doi.org/10.1111/j.1601-183X.2007.00378.x PubMedPubMedCentralGoogle Scholar
  119. 119.
    Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69(5):341–374PubMedGoogle Scholar
  120. 120.
    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237(4819):1154–1162PubMedGoogle Scholar
  121. 121.
    Arevalo JC, Wu SH (2006) Neurotrophin signaling: many exciting surprises! Cell Mol Life Sci 63(13):1523–1537.  https://doi.org/10.1007/s00018-006-6010-1 PubMedGoogle Scholar
  122. 122.
    Triaca V, Sposato V, Bolasco G, Ciotti MT, Pelicci P, Bruni AC, Cupidi C, Maletta R et al (2016) NGF controls APP cleavage by downregulating APP phosphorylation at Thr668: relevance for Alzheimer’s disease. Aging Cell.  https://doi.org/10.1111/acel.12473
  123. 123.
    Canu N, Amadoro G, Triaca V, Latina V, Sposato V, Corsetti V, Severini C, Ciotti MT et al (2017) The intersection of NGF/TrkA signaling and amyloid precursor protein processing in Alzheimer’s disease neuropathology. Int J Mol Sci 18(6).  https://doi.org/10.3390/ijms18061319
  124. 124.
    Peng S, Wuu J, Mufson EJ, Fahnestock M (2004) Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol 63(6):641–649PubMedGoogle Scholar
  125. 125.
    Mufson EJ, He B, Nadeem M, Perez SE, Counts SE, Leurgans S, Fritz J, Lah J et al (2012) Hippocampal proNGF signaling pathways and beta-amyloid levels in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol 71(11):1018–1029.  https://doi.org/10.1097/NEN.0b013e318272caab PubMedPubMedCentralGoogle Scholar
  126. 126.
    Fahnestock M, Michalski B, Xu B, Coughlin MD (2001) The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol Cell Neurosci 18(2):210–220.  https://doi.org/10.1006/mcne.2001.1016 PubMedGoogle Scholar
  127. 127.
    Fombonne J, Rabizadeh S, Banwait S, Mehlen P, Bredesen DE (2009) Selective vulnerability in Alzheimer’s disease: amyloid precursor protein and p75(NTR) interaction. Ann Neurol 65(3):294–303.  https://doi.org/10.1002/ana.21578 PubMedPubMedCentralGoogle Scholar
  128. 128.
    Carlo AS, Gustafsen C, Mastrobuoni G, Nielsen MS, Burgert T, Hartl D, Rohe M, Nykjaer A et al (2013) The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-beta peptide in the brain. J Neurosci: Off J Soc Neurosci 33(1):358–370.  https://doi.org/10.1523/JNEUROSCI.2425-12.2013 Google Scholar
  129. 129.
    Ernfors P, Henschen A, Olson L, Persson H (1989) Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2(6):1605–1613PubMedGoogle Scholar
  130. 130.
    Martinez-Murillo R, Caro L, Nieto-Sampedro M (1993) Lesion-induced expression of low-affinity nerve growth factor receptor-immunoreactive protein in Purkinje cells of the adult rat. Neuroscience 52(3):587–593PubMedGoogle Scholar
  131. 131.
    Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, Carter BD (2014) A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. J Biol Chem 289(31):21205–21216.  https://doi.org/10.1074/jbc.M114.563403 PubMedPubMedCentralGoogle Scholar
  132. 132.
    Roux PP, Colicos MA, Barker PA, Kennedy TE (1999) p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure. J Neurosci 19(16):6887–6896PubMedGoogle Scholar
  133. 133.
    Costantini C, Weindruch R, Della Valle G, Puglielli L (2005) A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochem J 391(Pt 1):59–67.  https://doi.org/10.1042/BJ20050700 PubMedPubMedCentralGoogle Scholar
  134. 134.
    Costantini C, Scrable H, Puglielli L (2006) An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation. EMBO J 25(9):1997–2006.  https://doi.org/10.1038/sj.emboj.7601062 PubMedPubMedCentralGoogle Scholar
  135. 135.
    Hu XY, Zhang HY, Qin S, Xu H, Swaab DF, Zhou JN (2002) Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Exp Neurol 178(1):104–111PubMedGoogle Scholar
  136. 136.
    Mufson EJ, Kordower JH (1992) Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease. Proc Natl Acad Sci U S A 89(2):569–573PubMedPubMedCentralGoogle Scholar
  137. 137.
    Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, Sun Y, Yang M et al (2011) p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci: Off J Soc Neurosci 31(6):2292–2304.  https://doi.org/10.1523/JNEUROSCI.2733-10.2011 Google Scholar
  138. 138.
    Chakravarthy B, Gaudet C, Menard M, Atkinson T, Brown L, Laferla FM, Armato U, Whitfield J (2010) Amyloid-beta peptides stimulate the expression of the p75(NTR) neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. J Alzheimers Dis: JAD 19(3):915–925.  https://doi.org/10.3233/JAD-2010-1288 PubMedGoogle Scholar
  139. 139.
    Salehi A, Ocampo M, Verhaagen J, Swaab DF (2000) P75 neurotrophin receptor in the nucleus basalis of meynert in relation to age, sex, and Alzheimer’s disease. Exp Neurol 161(1):245–258.  https://doi.org/10.1006/exnr.1999.7252 PubMedGoogle Scholar
  140. 140.
    Kordower JH, Gash DM, Bothwell M, Hersh L, Mufson EJ (1989) Nerve growth factor receptor and choline acetyltransferase remain colocalized in the nucleus basalis (Ch4) of Alzheimer’s patients. Neurobiol Aging 10(1):67–74PubMedGoogle Scholar
  141. 141.
    Goedert M, Fine A, Dawbarn D, Wilcock GK, Chao MV (1989) Nerve growth factor receptor mRNA distribution in human brain: normal levels in basal forebrain in Alzheimer’s disease. Brain Res Mol Brain Res 5(1):1–7PubMedGoogle Scholar
  142. 142.
    Treanor JJ, Dawbarn D, Allen SJ, MacGowan SH, Wilcock GK (1991) Low affinity nerve growth factor receptor binding in normal and Alzheimer’s disease basal forebrain. Neurosci Lett 121(1–2):73–76PubMedGoogle Scholar
  143. 143.
    Ginsberg SD, Che S, Wuu J, Counts SE, Mufson EJ (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J Neurochem 97(2):475–487.  https://doi.org/10.1111/j.1471-4159.2006.03764.x PubMedGoogle Scholar
  144. 144.
    Zeng F, Lu JJ, Zhou XF, Wang YJ (2011) Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol 82(10):1500–1509.  https://doi.org/10.1016/j.bcp.2011.06.040 PubMedGoogle Scholar
  145. 145.
    Coulson EJ, Nykjaer A (2013) Up-regulation of sortilin mediated by amyloid-beta and p75(NTR): safety lies in the middle course. J Neurochem 127(2):149–151.  https://doi.org/10.1111/jnc.12389 PubMedGoogle Scholar
  146. 146.
    Skeldal S, Sykes AM, Glerup S, Matusica D, Palstra N, Autio H, Boskovic Z, Madsen P et al (2012) Mapping of the interaction site between sortilin and the p75 neurotrophin receptor reveals a regulatory role for the sortilin intracellular domain in p75 neurotrophin receptor shedding and apoptosis. J Biol Chem 287(52):43798–43809.  https://doi.org/10.1074/jbc.M112.374710 PubMedPubMedCentralGoogle Scholar
  147. 147.
    Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci: Off J Soc Neurosci 25 (22):5455–5463. doi: https://doi.org/10.1523/JNEUROSCI.5123-04.2005
  148. 148.
    Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M et al (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427(6977):843–848.  https://doi.org/10.1038/nature02319 PubMedGoogle Scholar
  149. 149.
    Chen LW, Yung KK, Chan YS, Shum DK, Bolam JP (2008) The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson’s disease. CNS Neurol Disord Drug Targets 7(6):512–523PubMedGoogle Scholar
  150. 150.
    Mufson EJ, Ma SY, Dills J, Cochran EJ, Leurgans S, Wuu J, Bennett DA, Jaffar S et al (2002) Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 443(2):136–153PubMedGoogle Scholar
  151. 151.
    Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737–749PubMedGoogle Scholar
  152. 152.
    von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4(10):977–978.  https://doi.org/10.1038/nn730 Google Scholar
  153. 153.
    Greferath U, Bennie A, Kourakis A, Bartlett PF, Murphy M, Barrett GL (2000) Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice. Eur J Neurosci 12(3):885–893PubMedGoogle Scholar
  154. 154.
    Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG, Trieu J, Murphy M (2010) Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice. Hippocampus 20(1):145–152.  https://doi.org/10.1002/hipo.20598 PubMedGoogle Scholar
  155. 155.
    Naumann T, Casademunt E, Hollerbach E, Hofmann J, Dechant G, Frotscher M, Barde YA (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 22(7):2409–2418Google Scholar
  156. 156.
    Barrett GL, Naim T, Trieu J, Huang M (2016) In vivo knockdown of basal forebrain p75 neurotrophin receptor stimulates choline acetyltransferase activity in the mature hippocampus. J Neurosci Res 94(5):389–400.  https://doi.org/10.1002/jnr.23717 PubMedGoogle Scholar
  157. 157.
    Peterson DA, Dickinson-Anson HA, Leppert JT, Lee KF, Gage FH (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J Comp Neurol 404(1):1–20PubMedGoogle Scholar
  158. 158.
    Chao MV (2016) Cleavage of p75 neurotrophin receptor is linked to Alzheimer’s disease. Mol Psychiatry 21(3):300–301.  https://doi.org/10.1038/mp.2015.214 PubMedGoogle Scholar
  159. 159.
    Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35(7):431–440.  https://doi.org/10.1016/j.tins.2012.03.007 PubMedGoogle Scholar
  160. 160.
    Yao XQ, Jiao SS, Saadipour K, Zeng F, Wang QH, Zhu C, Shen LL, Zeng GH et al (2015) p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol Psychiatry 20(11):1301–1310.  https://doi.org/10.1038/mp.2015.49 PubMedPubMedCentralGoogle Scholar
  161. 161.
    Nguyen TV, Shen L, Vander Griend L, Quach LN, Belichenko NP, Saw N, Yang T, Shamloo M et al (2014) Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AbetaPP(L/S) transgenic mice. J Alzheimers Dis: JAD 42(2):459–483.  https://doi.org/10.3233/JAD-140036 PubMedPubMedCentralGoogle Scholar
  162. 162.
    Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, Zhang H, Yang T, Pollak J et al (2013) Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer’s mouse model. Neurobiol Aging 34(8):2052–2063.  https://doi.org/10.1016/j.neurobiolaging.2013.02.015 PubMedGoogle Scholar
  163. 163.
    Simmons DA, Belichenko NP, Ford EC, Semaan S, Monbureau M, Aiyaswamy S, Holman CM, Condon C et al (2016) A small molecule p75NTR ligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice. Hum Mol Genet.  https://doi.org/10.1093/hmg/ddw316
  164. 164.
    Ovsepian SV, Antyborzec I, O'Leary VB, Zaborszky L, Herms J, Oliver Dolly J (2014) Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Abeta) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. Brain Struct Funct 219(5):1527–1541.  https://doi.org/10.1007/s00429-013-0583-x PubMedGoogle Scholar
  165. 165.
    Barcelona PF, Saragovi HU (2015) A pro-nerve growth factor (proNGF) and NGF binding protein, alpha2-macroglobulin, differentially regulates p75 and TrkA receptors and is relevant to neurodegeneration ex vivo and in vivo. Mol Cell Biol 35(19):3396–3408.  https://doi.org/10.1128/MCB.00544-15 PubMedPubMedCentralGoogle Scholar
  166. 166.
    Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM (1997) alpha2-macroglobulin as a beta-amyloid peptide-binding plasma protein. J Neurochem 69(1):299–305PubMedGoogle Scholar
  167. 167.
    Mettenburg JM, Gonias SL (2005) Beta-amyloid peptide binds equivalently to binary and ternary alpha2-macroglobulin-protease complexes. Protein J 24(2):89–93PubMedGoogle Scholar
  168. 168.
    Hughes SR, Khorkova O, Goyal S, Knaeblein J, Heroux J, Riedel NG, Sahasrabudhe S (1998) Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. Proc Natl Acad Sci U S A 95(6):3275–3280PubMedPubMedCentralGoogle Scholar
  169. 169.
    Lauer D, Reichenbach A, Birkenmeier G (2001) Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism. Exp Neurol 167(2):385–392.  https://doi.org/10.1006/exnr.2000.7569 PubMedGoogle Scholar
  170. 170.
    Wyatt AR, Constantinescu P, Ecroyd H, Dobson CM, Wilson MR, Kumita JR, Yerbury JJ (2013) Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms. FEBS Lett 587(5):398–403.  https://doi.org/10.1016/j.febslet.2013.01.020 PubMedPubMedCentralGoogle Scholar
  171. 171.
    Tiveron C, Fasulo L, Capsoni S, Malerba F, Marinelli S, Paoletti F, Piccinin S, Scardigli R et al (2013) ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ 20(8):1017–1030.  https://doi.org/10.1038/cdd.2013.22 PubMedPubMedCentralGoogle Scholar
  172. 172.
    Capsoni S, Cattaneo A (2006) On the molecular basis linking nerve growth factor (NGF) to Alzheimer’s disease. Cell Mol Neurobiol 26(4–6):619–633.  https://doi.org/10.1007/s10571-006-9112-2 PubMedGoogle Scholar
  173. 173.
    Calissano P, Matrone C, Amadoro G (2010) Nerve growth factor as a paradigm of neurotrophins related to Alzheimer’s disease. Dev Neurobiol 70(5):372–383.  https://doi.org/10.1002/dneu.20759 PubMedGoogle Scholar
  174. 174.
    Calissano P, Amadoro G, Matrone C, Ciafre S, Marolda R, Corsetti V, Ciotti MT, Mercanti D et al (2010) Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF. Cell Death Differ 17(7):1126–1133.  https://doi.org/10.1038/cdd.2010.38 PubMedGoogle Scholar
  175. 175.
    Meeker RB, Williams KS (2015) The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen Res 10(5):721–725.  https://doi.org/10.4103/1673-5374.156967 PubMedPubMedCentralGoogle Scholar
  176. 176.
    Canu N, Pagano I, La Rosa LR, Pellegrino M, Ciotti MT, Mercanti D, Moretti F, Sposato V et al (2017) Association of TrkA and APP is promoted by NGF and reduced by cell death-promoting agents. Front Mol Neurosci 10:15.  https://doi.org/10.3389/fnmol.2017.00015 PubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Noralyn Basco Mañucat-Tan
    • 1
  • Khalil Saadipour
    • 2
  • Yan-Jiang Wang
    • 3
  • Larisa Bobrovskaya
    • 1
  • Zhou Xin-Fu 
    • 1
  1. 1.School of Pharmacy and Medical Sciences, Sansom Institute for Health ResearchUniversity of South AustraliaAdelaideAustralia
  2. 2.Departments of Cell Biology, Physiology and Neuroscience, and Psychiatry, Skirball Institute of Biomolecular MedicineNew York University Langone School of MedicineNew YorkUSA
  3. 3.Department of Neurology and Center for Clinical Neuroscience, Daping HospitalThird Military Medical UniversityChongqingChina

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