Molecular Neurobiology

, Volume 51, Issue 3, pp 1206–1220 | Cite as

Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

  • C. Vergara
  • L. Ordóñez-Gutiérrez
  • F. Wandosell
  • I. Ferrer
  • J. A. del Río
  • R. Gavín


Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic β-amyloid peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aβ oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrPC) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aβ are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrPC expression in the development of AD, and a putative relationship between PrPC and tau processing is emerging. However, the role of tau/PrPC interaction in AD is poorly understood. In this study, we show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrPC knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrPC expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrPC in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.


Alzheimer’s disease Microtubule-associated protein tau Cellular prion protein Aβ oligomers 



This research was supported by BESAD-P, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, for the laboratories of IF, JADR and FW. In addition, work in the laboratory of JADR was supported by grants from FP7-PRIORITY and DEMTEST (Joint Programming of Neurodegenerative Diseases, PI11/03028), Ministerio de Economía y Competitividad (MINECO) (BFU2012-32617), Generalitat de Catalunya (SGR2009-366 and SGR2014-1218), and Obra Social “La Caixa”. RG was supported by Fondo de Investigaciones Sanitarias (PI11-00075) and work in FW’s lab was supported by grants from the Direccion General de Ciencia y Tecnologia (DGCYT) (SAF2012-39148-C03-01), and EU-FP7-2009-(CT222887), as well as an institutional grant from the ‘Fundación Areces”. CV is supported by the Ministerio de Ciencia e Innovación (MICINN). The authors declare that they have no competing interests. We thank T. Yohannan for editorial assistance and M. Segura for technical assistance.

Supplementary material

12035_2014_8793_Fig6_ESM.jpg (400 kb)
Supplementary Fig. 1

a Electrophoretic characterization of different Aβ1-42 amyloid species. Peptide was matured under protocols for ADDLs or fibril formation prior to peptide culture treatments. Immunoblot was done with 6E10 monoclonal antibody. b, c TEM analysis of Aβ1-42 24 hours post-dissolution under oligomer- (b) or fibril-forming conditions (c). Scale bar: 200 nm. d Western blot analysis of total tau level or phosphorylated tau level (epitopes ser396/404, ser202/thr205, and thr181, respectively) in cortical cultures from Prnp 0/0, PrnP +/+ , and Tg20 mouse samples (n = 6, Prnp 0/0; n = 6 PrnP +/+ and n = 6 Tg20) after 24 hours of ADDL treatment. (JPEG 400 kb)

12035_2014_8793_Fig7_ESM.jpg (56 kb)
Supplementary Fig. 2

Comparative analysis of cortical primary culture from Prnp 0/0 mice treated with ADDLs or fibrillar Aβ1-42, respectively, for 6 hours (n = 3 ADDLs and n = 4 Aβ1-42). Note that tau expression increases only when cells are treated with oligomers. (JPEG 56 kb)

12035_2014_8793_Fig8_ESM.jpg (159 kb)
Supplementary Fig. 3

Characterization of the APP/PS1 mouse model used in this study. a-d Immunohistochemical analysis of 9-month-old animals with 4G8 monoclonal antibody for detection of amyloid plaques. Scale bars a, b, c = 200 μm Scale bar d = 40 μm. Abbreviations including H, hilus; GCL, granular cell layer; ML, molecular layer; SLM, stratum lacunosum-moleculare; SR, stratum radiatum; SP, stratum pyramidale; SO, stratum oriens; WM, white matter and I–VIb, neocortical layers. a Absence of amyloid plaques in brain sections of wild-type mice in contrast to Aβ deposits found in transgenic mice (b, c). d Higher magnification of the immunolabeled plaque framed in c. e Increasing levels of soluble Aβ1-42 amyloid with age quantified by ELISA. 9 animals were analyzed for each age. (JPEG 158 kb)


  1. 1.
    Moleres FJ, Velayos JL (2005) Expression of PrP(C) in the rat brain and characterization of a subset of cortical neurons. Brain Res 1056(1):10–21. doi: 10.1016/j.brainres.2005.06.067 CrossRefPubMedGoogle Scholar
  2. 2.
    Ford MJ, Burton LJ, Morris RJ, Hall SM (2002) Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 113(1):177–192CrossRefPubMedGoogle Scholar
  3. 3.
    Moser M, Colello RJ, Pott U, Oesch B (1995) Developmental expression of the prion protein gene in glial cells. Neuron 14(3):509–517CrossRefPubMedGoogle Scholar
  4. 4.
    Westergard L, Christensen HM, Harris DA (2007) The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochim Biophys Acta 1772(6):629–644CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science (New York, NY) 216(4542):136–144CrossRefGoogle Scholar
  6. 6.
    Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95(23):13363–13383CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Aguzzi A, Calella AM (2009) Prions: protein aggregation and infectious diseases. Physiol Rev 89(4):1105–1152. doi: 10.1152/physrev.00006.2009 89/4/1105 CrossRefPubMedGoogle Scholar
  8. 8.
    Braak H, Braak E (1996) Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol Scand Suppl 165:3–12CrossRefPubMedGoogle Scholar
  9. 9.
    Avila J (2000) Tau aggregation into fibrillar polymers: taupathies. FEBS Lett 476(1–2):89–92CrossRefPubMedGoogle Scholar
  10. 10.
    Avila J, Lucas JJ, Perez M, Hernandez F (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84(2):361–384. doi: 10.1152/physrev.00024.2003 CrossRefPubMedGoogle Scholar
  11. 11.
    Burack MA, Halpain S (1996) Site-specific regulation of Alzheimer-like tau phosphorylation in living neurons. Neuroscience 72(1):167–184CrossRefPubMedGoogle Scholar
  12. 12.
    Cruz JC, Tsai LH (2004) Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med 10(9):452–458. doi: 10.1016/j.molmed.2004.07.001 CrossRefPubMedGoogle Scholar
  13. 13.
    Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104(6):1433–1439. doi: 10.1111/j.1471-4159.2007.05194.x CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Seira O, Del Rio JA (2013) Glycogen synthase kinase 3 beta (GSK3beta) at the tip of neuronal development and regeneration. Mol Neurobiol. doi: 10.1007/s12035-013-8571-y PubMedGoogle Scholar
  15. 15.
    Sun X, Sato S, Murayama O, Murayama M, Park JM, Yamaguchi H, Takashima A (2002) Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett 321(1–2):61–64CrossRefPubMedGoogle Scholar
  16. 16.
    Plattner F, Angelo M, Giese KP (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem 281(35):25457–25465. doi: 10.1074/jbc.M603469200 CrossRefPubMedGoogle Scholar
  17. 17.
    Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J, Weber T, Kretzschmar HA, Poser S (1997) Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225(3):210–212CrossRefPubMedGoogle Scholar
  18. 18.
    Noguchi-Shinohara M, Hamaguchi T, Nozaki I, Sakai K, Yamada M (2011) Serum tau protein as a marker for the diagnosis of Creutzfeldt-Jakob disease. J Neurol. doi: 10.1007/s00415-011-5960-x PubMedGoogle Scholar
  19. 19.
    Wang GR, Shi S, Gao C, Zhang BY, Tian C, Dong CF, Zhou RM, Li XL, Chen C, Han J, Dong XP (2010) Changes of tau profiles in brains of the hamsters infected with scrapie strains 263 K or 139 A possibly associated with the alteration of phosphate kinases. BMC Infect Dis 10:86. doi: 10.1186/1471-2334-10-86 CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Perez M, Rojo AI, Wandosell F, Diaz-Nido J, Avila J (2003) Prion peptide induces neuronal cell death through a pathway involving glycogen synthase kinase 3. Biochem J 372(Pt 1):129–136. doi: 10.1042/BJ20021596 CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Lopes JP, Oliveira CR, Agostinho P (2009) Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-beta and prion peptides. Cell Cycle 8(1):97–104CrossRefPubMedGoogle Scholar
  22. 22.
    Nicolas O, Gavin R, del Rio JA (2009) New insights into cellular prion protein (PrPc) functions: the "ying and yang" of a relevant protein. Brain Res Rev 61(2):170–184. doi: 10.1016/j.brainresrev.2009.06.002 CrossRefPubMedGoogle Scholar
  23. 23.
    Osiecka KM, Nieznanska H, Skowronek KJ, Karolczak J, Schneider G, Nieznanski K (2009) Prion protein region 23-32 interacts with tubulin and inhibits microtubule assembly. Proteins 77(2):279–296. doi: 10.1002/prot.22435 CrossRefPubMedGoogle Scholar
  24. 24.
    Wang XF, Dong CF, Zhang J, Wan YZ, Li F, Huang YX, Han L, Shan B, Gao C, Han J, Dong XP (2008) Human tau protein forms complex with PrP and some GSS- and fCJD-related PrP mutants possess stronger binding activities with tau in vitro. Mol Cell Biochem 310(1–2):49–55. doi: 10.1007/s11010-007-9664-6 CrossRefPubMedGoogle Scholar
  25. 25.
    Alzualde A, Indakoetxea B, Ferrer I, Moreno F, Barandiaran M, Gorostidi A, Estanga A, Ruiz I, Calero M, van Leeuwen FW, Atares B, Juste R, Rodriguez-Martinez AB, Lopez de Munain A (2010) A novel PRNP Y218N mutation in Gerstmann-Straussler-Scheinker disease with neurofibrillary degeneration. J Neuropathol Exp Neurol 69(8):789–800. doi: 10.1097/NEN.0b013e3181e85737 CrossRefPubMedGoogle Scholar
  26. 26.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science (New York, NY) 256(5054):184–185CrossRefGoogle Scholar
  27. 27.
    Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. doi: 10.1038/nrd3505 nrd3505 CrossRefPubMedGoogle Scholar
  28. 28.
    Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95(11):6448–6453CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Bhatia R, Lin H, Lal R (2000) Fresh and globular amyloid beta protein (1-42) induces rapid cellular degeneration: evidence for AbetaP channel-mediated cellular toxicity. FASEB J: Off Publ Fed Am Soc Exp Biol 14(9):1233–1243Google Scholar
  30. 30.
    Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539. doi: 10.1038/416535a CrossRefPubMedGoogle Scholar
  31. 31.
    Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–1132. doi: 10.1038/nature07761 CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Lauren J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30(18):6367–6374. doi: 10.1523/JNEUROSCI.0395-10.2010 CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science (New York, NY) 316(5825):750–754. doi: 10.1126/science.1141736 CrossRefGoogle Scholar
  34. 34.
    Williamson R, Usardi A, Hanger DP, Anderton BH (2008) Membrane-bound beta-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB J: Off Publ Fed Am Soc Exp Biol 22(5):1552–1559. doi: 10.1096/fj.07-9766com CrossRefGoogle Scholar
  35. 35.
    Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J (2002) Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau. J Neurosci: Off J Soc Neurosci 22(3):698–707Google Scholar
  36. 36.
    Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM, Kellermann O (2000) Signal transduction through prion protein. Science (New York, NY) 289(5486):1925–1928Google Scholar
  37. 37.
    Gavin R, Braun N, Nicolas O, Parra B, Urena JM, Mingorance A, Soriano E, Torres JM, Aguzzi A, del Rio JA (2005) PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc. FEBS Lett 579(19):4099–4106. doi: 10.1016/j.febslet.2005.06.037 CrossRefPubMedGoogle Scholar
  38. 38.
    Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H (2004) Phosphorylation of tau by fyn: implications for Alzheimer's disease. J Neurosci: Off J Soc Neurosci 24(9):2304–2312. doi: 10.1523/JNEUROSCI.4162-03.2004 CrossRefGoogle Scholar
  39. 39.
    Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci Off J Soc Neurosci 31(2):700–711. doi: 10.1523/JNEUROSCI.4152-10.2011 CrossRefGoogle Scholar
  40. 40.
    Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15(9):1227–1235. doi: 10.1038/nn.3178 CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA, Bennett DA, Aguzzi A, Lesne SE (2012) The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer's disease. J Neurosci 32(47):16857–16871a. doi: 10.1523/JNEUROSCI.1858-12.2012 CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Um JW, Strittmatter SM (2013) Amyloid-beta induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion 7(1):37–41. doi: 10.4161/pri.22212 22212 CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Velayos JL, Irujo A, Cuadrado-Tejedor M, Paternain B, Moleres FJ, Ferrer V (2009) The cellular prion protein and its role in Alzheimer disease. Prion 3(2):110–117CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    McNeill A (2004) A molecular analysis of prion protein expression in Alzheimer’s disease. McGill J Med 8:7–14Google Scholar
  45. 45.
    Rezaie P, Pontikis CC, Hudson L, Cairns NJ, Lantos PL (2005) Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer’s disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study. J Histochem Cytochem 53(8):929–940. doi: 10.1369/jhc.4A6551.2005 CrossRefPubMedGoogle Scholar
  46. 46.
    Griffiths HH, Whitehouse IJ, Hooper NM (2012) Regulation of amyloid-beta production by the prion protein. Prion 6(3):217–222. doi: 10.4161/pri.18988 CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356(6370):577–582CrossRefPubMedGoogle Scholar
  48. 48.
    Fischer M, Rulicke T, Raeber A, Sailer A, Moser M, Oesch B, Brandner S, Aguzzi A, Weissmann C (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15(6):1255–1264PubMedCentralPubMedGoogle Scholar
  49. 49.
    Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD (2006) Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A 103(9):3416–3421CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17(6):157–165CrossRefPubMedGoogle Scholar
  51. 51.
    Pratt T, Sharp L, Nichols J, Price DJ, Mason JO (2000) Embryonic stem cells and transgenic mice ubiquitously expressing a tau-tagged green fluorescent protein. Dev Biol 228(1):19–28. doi: 10.1006/dbio.2000.9935 CrossRefPubMedGoogle Scholar
  52. 52.
    Braak H, Braak E, Bohl J, Bratzke H (1998) Evolution of Alzheimer’s disease related cortical lesions. J Neural Transm Suppl 54:97–106CrossRefPubMedGoogle Scholar
  53. 53.
    Huijbers W, Mormino EC, Wigman SE, Ward AM, Vannini P, McLaren DG, Becker JA, Schultz AP, Hedden T, Johnson KA, Sperling RA (2014) Amyloid deposition is linked to aberrant entorhinal activity among cognitively normal older adults. J Neurosci 34(15):5200–5210. doi: 10.1523/JNEUROSCI.3579-13.2014 CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Abad MA, Enguita M, DeGregorio-Rocasolano N, Ferrer I, Trullas R (2006) Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer’s brain. J Neurosci 26(49):12735–12747. doi: 10.1523/JNEUROSCI.0575-06.2006 CrossRefPubMedGoogle Scholar
  55. 55.
    Klein WL (2002) Abeta toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 41(5):345–352CrossRefPubMedGoogle Scholar
  56. 56.
    Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685CrossRefPubMedGoogle Scholar
  57. 57.
    Hanger DP, Gibb GM, de Silva R, Boutajangout A, Brion JP, Revesz T, Lees AJ, Anderton BH (2002) The complex relationship between soluble and insoluble tau in tauopathies revealed by efficient dephosphorylation and specific antibodies. FEBS Lett 531(3):538–542CrossRefPubMedGoogle Scholar
  58. 58.
    McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L, Leverenz J, Schellenberg GD, D’Souza I (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol 511(6):788–803. doi: 10.1002/cne.21867 CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Bribian A, Fontana X, Llorens F, Gavin R, Reina M, Garcia-Verdugo JM, Torres JM, de Castro F, del Rio JA (2012) Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS. PLoS One 7(4):e33872. doi: 10.1371/journal.pone.0033872 CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. doi: 10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  61. 61.
    Carulla P, Bribian A, Rangel A, Gavin R, Ferrer I, Caelles C, Del Rio JA, Llorens F (2011) Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding. Mol Biol Cell 22(17):3041–3054. doi: 10.1091/mbc.E11-04-0321 CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Gotz J, Gladbach A, Pennanen L, van Eersel J, Schild A, David D, Ittner LM (2010) Animal models reveal role for tau phosphorylation in human disease. Biochim Biophys Acta 1802(10):860–871. doi: 10.1016/j.bbadis.2009.09.008 CrossRefPubMedGoogle Scholar
  63. 63.
    De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9):1334–1347. doi: 10.1016/j.neurobiolaging.2007.02.029 CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Bulbarelli A, Lonati E, Cazzaniga E, Gregori M, Masserini M (2009) Pin1 affects Tau phosphorylation in response to Abeta oligomers. Mol Cell Neurosci 42(1):75–80. doi: 10.1016/j.mcn.2009.06.001 CrossRefPubMedGoogle Scholar
  65. 65.
    Llorens F, Ferrer I, Del Rio JA (2013) Gene expression resulting from PrP ablation and PrP overexpression in murine and cellular models. Mol Neurobiol. doi: 10.1007/s12035-013-8529-0 PubMedGoogle Scholar
  66. 66.
    Nuvolone M, Kana V, Hutter G, Sakata D, Mortin-Toth SM, Russo G, Danska JS, Aguzzi A (2013) SIRPalpha polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells. J Exp Med 210(12):2539–2552. doi: 10.1084/jem.20131274 CrossRefPubMedCentralPubMedGoogle Scholar
  67. 67.
    Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24(3):516–524. doi: 10.1016/j.nbd.2006.08.017 CrossRefPubMedGoogle Scholar
  68. 68.
    Kurt MA, Davies DC, Kidd M, Duff K, Howlett DR (2003) Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Neurobiol Dis 14(1):89–97CrossRefPubMedGoogle Scholar
  69. 69.
    Ordonez-Gutierrez L, Torres JM, Gavin R, Anton M, Arroba-Espinosa AI, Espinosa JC, Vergara C, Del Rio JA, Wandosell F (2013) Cellular prion protein modulates beta-amyloid deposition in aged APP/PS1 transgenic mice. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2013.05.019 PubMedGoogle Scholar
  70. 70.
    Llorens F, Ansoleaga B, Garcia-Esparcia P, Zafar S, Grau-Rivera O, Lopez-Gonzalez I, Blanco R, Carmona M, Yague J, Nos C, Del Rio JA, Gelpi E, Zerr I, Ferrer I (2013) PrP mRNA and protein expression in brain and PrP in CSF in Creutzfeldt-Jakob disease MM1 and VV2. Prion 7(5):383–393CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Whitehouse IJ, Miners JS, Glennon EB, Kehoe PG, Love S, Kellett KA, Hooper NM (2013) Prion protein is decreased in Alzheimer’s brain and inversely correlates with BACE1 activity, amyloid-beta levels and Braak stage. PLoS One 8(4):e59554. doi: 10.1371/journal.pone.0059554 CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    Benvegnu S, Roncaglia P, Agostini F, Casalone C, Corona C, Gustincich S, Legname G (2011) Developmental influence of the cellular prion protein on the gene expression profile in mouse hippocampus. Physiol Genomics 43(12):711–725. doi: 10.1152/physiolgenomics.00205.2010 CrossRefPubMedGoogle Scholar
  73. 73.
    Rangel A, Madronal N, Gruart A, Gavin R, Llorens F, Sumoy L, Torres JM, Delgado-Garcia JM, Del Rio JA (2009) Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice. PLoS One 4(10):e7592. doi: 10.1371/journal.pone.0007592 CrossRefPubMedCentralPubMedGoogle Scholar
  74. 74.
    Schmitz M, Wulf K, Signore SC, Schulz-Schaeffer WJ, Kermer P, Bahr M, Wouters FS, Zafar S, Zerr I (2014) Impact of the cellular prion protein on amyloid-beta and 3PO-Tau processing. J Alzheimers Dis 38(3):551–565. doi: 10.3233/JAD-130566 PubMedGoogle Scholar
  75. 75.
    Chen RJ, Chang WW, Lin YC, Cheng PL, Chen YR (2013) Alzheimer’s amyloid-beta oligomers rescue cellular prion protein induced tau reduction via Fyn pathways. ACS Chem Neurosci. doi: 10.1021/cn400085q Google Scholar
  76. 76.
    Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM, Kellermann O (2000) Signal transduction through prion protein. Science (New York, NY) 289(5486):1925–1928CrossRefGoogle Scholar
  77. 77.
    Zhao Y, Zhao B (2013) Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013:316523. doi: 10.1155/2013/316523 PubMedCentralPubMedGoogle Scholar
  78. 78.
    Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938–11950. doi: 10.1523/JNEUROSCI.2357-10.2010 CrossRefPubMedGoogle Scholar
  79. 79.
    Steele AD, Zhou Z, Jackson WS, Zhu C, Auluck P, Moskowitz MA, Chesselet MF, Lindquist S (2009) Context dependent neuroprotective properties of prion protein (PrP). Prion 3(4):240–249CrossRefPubMedCentralPubMedGoogle Scholar
  80. 80.
    de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73(4):685–697. doi: 10.1016/j.neuron.2011.11.033 CrossRefPubMedCentralPubMedGoogle Scholar
  81. 81.
    Schwarze-Eicker K, Keyvani K, Gortz N, Westaway D, Sachser N, Paulus W (2005) Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging 26(8):1177–1182. doi: 10.1016/j.neurobiolaging.2004.10.004 CrossRefPubMedGoogle Scholar
  82. 82.
    Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM (2007) Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc Natl Acad Sci U S A 104(26):11062–11067. doi: 10.1073/pnas.0609621104 CrossRefPubMedCentralPubMedGoogle Scholar
  83. 83.
    Ferrer I, Blanco R, Carmona M, Puig B, Ribera R, Rey MJ, Ribalta T (2001) Prion protein expression in senile plaques in Alzheimer’s disease. Acta Neuropathol 101(1):49–56PubMedGoogle Scholar
  84. 84.
    Takahashi RH, Tobiume M, Sato Y, Sata T, Gouras GK, Takahashi H (2011) Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer’s disease brain. Neuropathology 31(3):208–214. doi: 10.1111/j.1440-1789.2010.01158.x CrossRefPubMedGoogle Scholar
  85. 85.
    Brown DR, Schulz-Schaeffer WJ, Schmidt B, Kretzschmar HA (1997) Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD-1 activity. Exp Neurol 146(1):104–112CrossRefPubMedGoogle Scholar
  86. 86.
    Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1(3):213–216CrossRefPubMedGoogle Scholar
  87. 87.
    Avila J (2010) Intracellular and extracellular tau. Front Neurosci 4:49. doi: 10.3389/fnins.2010.00049 CrossRefPubMedCentralPubMedGoogle Scholar
  88. 88.
    Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25(22):5446–5454. doi: 10.1523/JNEUROSCI.4637-04.2005 CrossRefPubMedGoogle Scholar
  89. 89.
    Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622. doi: 10.1016/S1474-4422(13)70090-5 CrossRefPubMedGoogle Scholar
  90. 90.
    Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Gotz J (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142(3):387–397. doi: 10.1016/j.cell.2010.06.036 CrossRefPubMedGoogle Scholar
  91. 91.
    Shirazi SK, Wood JG (1993) The protein tyrosine kinase, fyn, in Alzheimer’s disease pathology. Neuroreport 4(4):435–437CrossRefPubMedGoogle Scholar
  92. 92.
    Mattei V, Garofalo T, Misasi R, Circella A, Manganelli V, Lucania G, Pavan A, Sorice M (2004) Prion protein is a component of the multimolecular signaling complex involved in T cell activation. FEBS Lett 560(1–3):14–18. doi: 10.1016/S0014-5793(04)00029-8 CrossRefPubMedGoogle Scholar
  93. 93.
    Vega IE, Cui L, Propst JA, Hutton ML, Lee G, Yen SH (2005) Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res 138(2):135–144. doi: 10.1016/j.molbrainres.2005.04.015 CrossRefGoogle Scholar
  94. 94.
    Poppek D, Keck S, Ermak G, Jung T, Stolzing A, Ullrich O, Davies KJ, Grune T (2006) Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. Biochem J 400(3):511–520. doi: 10.1042/BJ20060463 CrossRefPubMedCentralPubMedGoogle Scholar
  95. 95.
    Canu N, Filesi I, Pristera A, Ciotti MT, Biocca S (2011) Altered intracellular distribution of PrPC and impairment of proteasome activity in tau overexpressing cortical neurons. J Alzheimers Dis 27(3):603–613. doi: 10.3233/JAD-2011-110446 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • C. Vergara
    • 1
    • 2
  • L. Ordóñez-Gutiérrez
    • 2
    • 4
  • F. Wandosell
    • 2
    • 4
  • I. Ferrer
    • 2
    • 5
  • J. A. del Río
    • 1
    • 2
    • 3
  • R. Gavín
    • 1
    • 2
    • 3
  1. 1.Molecular and Cellular NeurobiotechnologyInstitute for Bioengineering of CataloniaBarcelonaSpain
  2. 2.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  3. 3.Department of Cell Biology, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain
  4. 4.Centro de Biología Molecular Severo Ochoa, Cabrera 1, CBM-UAMMadridSpain
  5. 5.Institute of Neuropathology, IDIBELL-Hospital Universitari de Bellvitge, Faculty of MedicineUniversity of BarcelonaHospitalet de LlobregatSpain

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