Skip to main content

Advertisement

SpringerLink
Log in

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Patients suffering from tauopathies including frontotemporal dementia (FTD) and Alzheimer’s disease (AD) present with intra-neuronal aggregation of microtubule-associated protein Tau. During the disease process, Tau undergoes excessive phosphorylation, dissociates from microtubules and aggregates into insoluble neurofibrillary tangles (NFTs), accumulating in the soma. While many aspects of the disease pathology have been replicated in transgenic mouse models, a region-specific non-transgenic expression model is missing. Complementing existing models, we here report a novel region-specific approach to modelling Tau pathology. Local co-administration of the pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) extracted from marine sponges, and synthetic full-length 4R recombinant human Tau (hTau) was performed in vitro and in vivo. At low doses, Poly-APS was non-toxic and cultured cells exposed to Poly-APS (0.5 µg/ml) and hTau (1 µg/ml; ~22 µM) had normal input resistance, resting-state membrane potentials and Ca2+ transients induced either by glutamate or KCl, as did cells exposed to a low concentration of the phosphatase inhibitor Okadaic acid (OA; 1 nM, 24 h). Combined hTau loading and phosphatase inhibition resulted in a collapse of the membrane potential, suppressed excitation and diminished glutamate and KCl-stimulated Ca2+ transients. Stereotaxic infusions of Poly-APS (0.005 µg/ml) and hTau (1 µg/ml) bilaterally into the dorsal hippocampus at multiple sites resulted in hTau loading of neurons in rats. A separate cohort received an additional 7-day minipump infusion of OA (1.2 nM) intrahippocampally. When tested 2 weeks after surgery, rats treated with Poly-APS+hTau+OA presented with subtle learning deficits, but were also impaired in cognitive flexibility and recall. Hippocampal plasticity recorded from slices ex vivo was diminished in Poly-APS+hTau+OA subjects, but not in other treatment groups. Histological sections confirmed the intracellular accumulation of hTau in CA1 pyramidal cells and along their processes; phosphorylated Tau was present only within somata. This study demonstrates that cognitive, physiological and pathological symptoms reminiscent of tauopathies can be induced following non-mutant hTau delivery into CA1 in rats, but functional consequences hinge on increased Tau phosphorylation. Collectively, these data validate a novel model of locally infused recombinant hTau protein as an inducer of Tau pathology in the hippocampus of normal rats; future studies will provide insights into the pathological spread and maturation of Tau pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Pryer NK, Walker RA, Skeen VP, Bourns BD, Soboeiro MF, Salmon ED (1992) Brain microtubule-associated proteins modulate microtubule dynamic instability in vitro Real-time observations using video microscopy. J cell Sci 103(4):965–976

    CAS  PubMed  Google Scholar 

  2. Niewiadomska G, Baksalerska-pazera M, Lenarcik I (1996) Riedel G (2006) Compartmental protein expression of Tau, GSK-3beta and TrkA in cholinergic neurons of aged rats. J Neural Transm Vienna Austria 113(11):1733–1746

    Article  CAS  Google Scholar 

  3. Spillantini MG, Goedert M (2000) Tau mutations in familial frontotemporal dementia. Brain J Neurol 123(5):857–859

    Article  Google Scholar 

  4. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99(9):6364–6369

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein Tau. Proc Natl Acad Sci USA 85(11):4051–4055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Crowther RA (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci USA 88(6):2288–2292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60(9):1495–1500

    Article  CAS  PubMed  Google Scholar 

  8. Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60(5):729–736

    Article  PubMed  Google Scholar 

  9. Morishima-kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y (1995) Hyperphosphorylation of Tau in PHF. Neurobiol Aging 16(3):365–371 (discussion 371–80)

    Article  CAS  PubMed  Google Scholar 

  10. Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and Tau sites involved in Alzheimer neurofibrillary degeneration. The European journal of neuroscience 25(1):59–68

    Article  PubMed Central  PubMed  Google Scholar 

  11. Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, Bird IN, Varndell IM, Sheppard PW, Everall I, Anderton BH (2002) Rapid tyrosine phosphorylation of neuronal proteins including Tau and focal adhesion kinase in response to amyloid-beta peptide exposure: involvement of Src family protein kinases. J Neurosci Off J Soc Neurosci 22(1):10–20

    CAS  Google Scholar 

  12. 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

    Article  CAS  Google Scholar 

  13. Derkinderen P, Scales TM, Hanger DP, Leung KY, Byers HL, Ward MA, Lenz C, Price C, Bird IN, Perera T, Kellie S, Williamson R, Noble W, van Etten RA, Leroy K, Brion JP, Reynolds CH, Anderton BH (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament Tau and in fetal Tau with c-Abl as the candidate tyrosine kinase. J Neurosci Off J Soc Neurosci 25(28):6584–6593

    Article  CAS  Google Scholar 

  14. Mietelska-Porowska A, Wasik U, Goras M, Filipek A, Niewiadomska G (2014) Tau protein modifications and interactions: their role in function and dysfunction. Int J Mol Sci 15(3):4671–4713

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40(3):471–483

    Article  CAS  PubMed  Google Scholar 

  16. Braak H, Braak E (1996) Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol Scand Suppl 165:3–12

    Article  CAS  PubMed  Google Scholar 

  17. Lauckner J, Frey P, Geula C (2003) Comparative distribution of Tau phosphorylated at Ser262 in pre-tangles and tangles. Neurobiol Aging 24(6):767–776

    Article  CAS  PubMed  Google Scholar 

  18. Biernat J, Mandelkow EM (1999) The development of cell processes induced by Tau protein requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains. Mol Biol Cell 10(3):727–740

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007) Accumulation of pathological Tau species and memory loss in a conditional model of tauopathy. J Neurosci Off J Soc Neurosci 27(14):3650–3662

    Article  CAS  Google Scholar 

  20. Flunkert S, Hierzer M, Loffler T, Rabl R, Neddens J, Duller S, Schofield EL, Ward MA, Posch M, Jungwirth H, Windisch M, Hutter-Paier B (2013) Elevated levels of soluble total and hyperphosphorylated Tau result in early behavioral deficits and distinct changes in brain pathology in a new Tau transgenic mouse model. Neuro-degenerative diseases 11(4):194–205

    Article  CAS  PubMed  Google Scholar 

  21. Fox LM, William CM, Adamowicz DH, Pitstick R, Carlson GA, Spires-Jones TL, Hyman BT (2011) Soluble Tau species, not neurofibrillary aggregates, disrupt neural system integration in a Tau transgenic model. J Neuropathol Exp Neurol 70(7):588–595

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, Deture M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Sci (New York, NY) 309(5733):476–481

    Article  CAS  Google Scholar 

  23. Sydow A, Mandelkow EM (2010) ‘Prion-like’ propagation of mouse and human Tau aggregates in an inducible mouse model of tauopathy. Neuro-degenerative Dis 7(1–3):28–31

    Article  CAS  Google Scholar 

  24. Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to Tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer’s disease. J Neurosci Off J Soc Neurosci 24(10):2401–2411

    Article  CAS  Google Scholar 

  25. Zhu D, Kosik KS, Meigs TE, Yanamadala V, Denker BM (2004) Galpha12 directly interacts with PP2A: evidence FOR Galpha12-stimulated PP2A phosphatase activity and dephosphorylation of microtubule-associated protein Tau. J Biol Chem 279(53):54983–54986

    Article  CAS  PubMed  Google Scholar 

  26. Sontag E, Nunbhakdi-Craig V, Bloom GS, Mumby MC (1995) A novel pool of protein phosphatase 2A is associated with microtubules and is regulated during the cell cycle. J Cell Biol 128(6):1131–1144

    Article  CAS  PubMed  Google Scholar 

  27. Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC (1996) Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 17(6):1201–1207

    Article  CAS  PubMed  Google Scholar 

  28. Liao H, Li Y, Brautigan DL, Gundersen GG (1998) Protein phosphatase 1 is targeted to microtubules by the microtubule-associated protein Tau. J Biol Chem 273(34):21901–21908

    Article  CAS  PubMed  Google Scholar 

  29. Gong CX, Liu F, Wu G, Rossie S, Wegiel J, Li L, Grundke-Iqbal I, Iqbal K (2004) Dephosphorylation of microtubule-associated protein Tau by protein phosphatase 5. J Neurochem 88(2):298–310

    Article  CAS  PubMed  Google Scholar 

  30. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of Tau phosphorylation. Eur J Neurosci 22(8):1942–1950

    Article  PubMed  Google Scholar 

  31. Sontag E, Hladik C, Montgomery L, Luangpirom A, Mudrak I, Ogris E, White CL III (2004) Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol 63(10):1080–1091

    CAS  PubMed  Google Scholar 

  32. Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, White CL III (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 63(4):287–301

    CAS  PubMed  Google Scholar 

  33. Tanimukai H, Grundke-Iqbal I, Iqbal K (2005) Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am J Pathol 166(6):1761–1771

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C, White CL III, Sontag E (2000) Reduced binding of protein phosphatase 2A to Tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J Neurochem 75(5):2155–2162

    Article  CAS  PubMed  Google Scholar 

  35. Li R, Xu DE, Ma T (2015) Lovastatin suppresses the aberrant tau phosphorylation from FTDP-17 mutation and okadaic acid-induction in rat primary neurons. Neuroscience 294:14–20

    Article  CAS  PubMed  Google Scholar 

  36. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259

    Article  CAS  PubMed  Google Scholar 

  37. Melis V, Zabke C, Stamer K, Magbagbeolu M, Schwab K, Marschall P, Veh RW, Bachmann S, Deiana S, Moreau P, Davidson K, Harrington KA, Rickard JE, Horsley D, Garman R, Mazurkiewicz M, Niewiadomska G, Wischik CM, Harrington CR, Riedel G, Theuring F (2014) Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration. Cell Mol Life Sci CMLS. doi:10.1007/s00018-014-1804-z

    PubMed  Google Scholar 

  38. Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70(4):532–540

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, Dearmond SJ, Prusiner SB, Giles K (2012) Purified and synthetic Alzheimer’s amyloid beta (Abeta) prions. Proc Natl Acad Sci USA 109(27):11025–11030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3):337–351

    Article  CAS  PubMed  Google Scholar 

  42. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E, Van Acker N, Kemp JA, Mercken M, Brunden KR, Trojanowski JQ, Dewachter I, Lee VM, Moechars D (2015) Intracerebral injection of preformed synthetic Tau fibrils initiates widespread tauopathy and neuronal loss in the brains of Tau transgenic mice. Neurobiol Dis 73:83–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Dujardin S, Lecolle K, Caillierez R, Begard S, Zommer N, Lachaud C, Carrier S, Dufour N, Auregan G, Winderickx J, Hantraye P, Deglon N, Colin M, Buee L (2014) Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol Commun 2:14

    Article  PubMed Central  PubMed  Google Scholar 

  44. Do Carmo S, Cuello AC (2013) Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8:37

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Lin JH (1995) Species similarities and differences in pharmacokinetics. Drug metabolism and disposition: the biological fate of chemicals 23(10):1008–1021

    CAS  Google Scholar 

  46. Jacob HJ, Kwitek AE (2002) Rat genetics: attaching physiology and pharmacology to the genome. Nat Rev Genet 3(1):33–42

    Article  CAS  PubMed  Google Scholar 

  47. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M (2009) Rat Tau proteome consists of six Tau isoforms: implication for animal models of human tauopathies. J Neurochem 108(5):1167–1176

    Article  CAS  PubMed  Google Scholar 

  49. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130

    Article  CAS  PubMed  Google Scholar 

  50. Braak E, Braak H (1997) Alzheimer’s disease: transiently developing dendritic changes in pyramidal cells of sector CA1 of the Ammon’s horn. Acta Neuropathol 93(4):323–325

    Article  CAS  PubMed  Google Scholar 

  51. Cehlar O, Skrabana R, Kovac A, Kovacech B, Novak M (2012) Crystallization and preliminary X-ray diffraction analysis of Tau protein microtubule-binding motifs in complex with Tau5 and DC25 antibody Fab fragments. Acta Crystallogr Sect F Struct Biol Cryst Commun 68(10):1181–1185

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Sepcic K, Batista U, Vacelet J, Macek P, Turk T (1997) Biological activities of aqueous extracts from marine sponges and cytotoxic effects of 3-alkylpyridinium polymers from Reniera sarai Comparative biochemistry and physiologyPart C. Pharmacol Toxicol Endocrinol 117(1):47–53

    CAS  Google Scholar 

  53. McClelland D, Evans RM, Abidin I, Sharma S, Choudhry FZ, Jaspars M, Sepcic K, Scott RH (2003) Irreversible and reversible pore formation by polymeric alkylpyridinium salts (poly-APS) from the sponge Reniera sarai. Br J Pharmacol 139(8):1399–1408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Tucker SJ, McClelland D, Jaspars M, Sepcic K, Macewan DJ, Scott RH (2003) The influence of alkyl pyridinium sponge toxins on membrane properties, cytotoxicity, transfection and protein expression in mammalian cells. Biochim Biophys Acta 1614(2):171–181

    Article  CAS  PubMed  Google Scholar 

  55. Koss DJ, Hindley KP, David KC, Mancini I, Guella G, Sepcic K, Turk T, Rebolj K, Riedel G, Platt B, Scott RH (2007) A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones. BMC Pharmacol 7:1

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Malovrh P, Sepcic K, Turk T, Macek P (1999) Characterization of hemolytic activity of 3-alkylpyridinium polymers from the marine sponge Reniera sarai Comparative biochemistry and physiologyPart C. Pharmacol Toxicol Endocrinol 124(2):221–226

    CAS  Google Scholar 

  57. Schmitz FJ, Hollenbeak KH, Campbell DC (1978) Marine natural products: halitoxin, toxic complex of several marine sponges of the genus Haliclona. J Org Chem 43:3916–3922

    Article  CAS  Google Scholar 

  58. Berlinck RG, Ogawa CA, Almeida AM, Sanchez MA, Malpezzi EL, Costa LV, Hajdu E, De Freitas JC (1996) Chemical and pharmacological characterization of halitoxin from Amphimedon viridis (Porifera) from the southeastern Brazilian coast Comparative biochemistry and physiology Part C. Pharmacol Toxicol Endocrinol 115(2):155–163

    CAS  Google Scholar 

  59. Scott RH, Whyment AD, Foster A, Gordon KH, Milne BF, Jaspars M (2000) Analysis of the structure and electrophysiological actions of halitoxins: 1,3 alkyl-pyridinium salts from Callyspongia ridleyi. J Membr Biol 176(2):119–131

    Article  CAS  PubMed  Google Scholar 

  60. Sepcic K, Guella G, Mancini I, Pietra F, Serra MD, Menestrina G, Tubbs K, Macek P, Turk T (1997) Characterization of anticholinesterase-active 3-alkylpyridinium polymers from the marine sponge Reniera sarai in aqueous solutions. J Nat Prod 60(10):991–996

    Article  CAS  PubMed  Google Scholar 

  61. Davies-Coleman MT, Faulkner DJ, Dubowchik GM, Roth GP, Polson C, Fairchild C (1993) A New EGF-Active Polymeric Pyridinium Alkaloid from the Sponge Callyspongia fibrosa. J Org Chem 58:5925–5930

    Article  CAS  Google Scholar 

  62. Koss DJ, Hindley KP, Riedel G, Platt B (2007) Modulation of hippocampal calcium signalling and plasticity by serine/threonine protein phosphatases. J Neurochem 102(4):1009–1023

    Article  CAS  PubMed  Google Scholar 

  63. Koss DJ, Riedel G, Platt B (2009) Intracellular Ca2 + stores modulate SOCCs and NMDA receptors via tyrosine kinases in rat hippocampal neurons. Cell Calcium 46(1):39–48

    Article  CAS  PubMed  Google Scholar 

  64. Scharschmidt BF, Lake JR, Renner EL, Licko V, van Dyke RW (1986) Fluid phase endocytosis by cultured rat hepatocytes and perfused rat liver: implications for plasma membrane turnover and vesicular trafficking of fluid phase markers. Proc Natl Acad Sci USA 83(24):9488–9492

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391(2):85–100

    Article  CAS  PubMed  Google Scholar 

  66. Riedel G, Micheau J, Lam AG, Roloff EL, Martin SJ, Bridge H, de Hoz L, Poeschel B, McCulloch J, Morris RG (1999) Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 2(10):898–905

    Article  CAS  PubMed  Google Scholar 

  67. Robinson L, McKillop-Smith S, Ross NL, Pertwee RG, Hampson RE, Platt B, Riedel G (2008) Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats. Psychopharmacology 198(4):551–563

    Article  CAS  PubMed  Google Scholar 

  68. Christie LA, Riedel G, Algaidi SA, Whalley LJ, Platt B (2005) Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine. Neurosci Lett 373(2):119–124

    Article  CAS  PubMed  Google Scholar 

  69. Koss DJ, Drever BD, Stoppelkamp S, Riedel G, Platt B (2013) Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1(Triple) Alzheimer mouse. Cellular and molecular life sciences : CMLS 70(14):1273–1279

    Article  CAS  Google Scholar 

  70. Algaidi SA, Christie LA, Jenkinson AM, Whalley L, Riedel G, Platt B (2006) Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity. Exp Neurol 197(1):8–21

    Article  CAS  PubMed  Google Scholar 

  71. Niewiadomska G, Baksalerska-Pazera M, Riedel G (2006) Cytoskeletal transport in the aging brain: focus on the cholinergic system. Rev Neurosci 17(6):581–618

    CAS  PubMed  Google Scholar 

  72. Mudher AK, Perry VH (1998) Using okadaic acid as a tool for the in vivo induction of hyperphosphorylated Tau. Neuroscience 85(4):1329–1332

    Article  CAS  PubMed  Google Scholar 

  73. van Dam AM, Bol JG, Binnekade R, van Muiswinkel FL (1998) Acute or chronic administration of okadaic acid to rats induces brain damage rather than Alzheimer-like neuropathology. Neuroscience 85(4):1333–1335

    Article  PubMed  Google Scholar 

  74. Dayton RD, Wang DB, Cain CD, Schrott LM, Ramirez JJ, King MA, Klein RL (2012) Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus. Exp Neurol 233(2):807–814

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM (2013) Anti-Tau antibodies that block Tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80(2):402–414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. McLaggan D, Adjimatera N, Sepcic K, Jaspars M, Macewan DJ, Blagbrough IS, Scott RH (2006) Pore forming polyalkylpyridinium salts from marine sponges versus synthetic lipofection systems: distinct tools for intracellular delivery of cDNA and siRNA. BMC Biotechnol 6:6

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Paleari L, Trombino S, Falugi C, Gallus L, Carlone S, Angelini C, Sepcic K, Turk T, Faimali M, Noonan DM, Albini A (2006) Marine sponge-derived polymeric alkylpyridinium salts as a novel tumor chemotherapeutic targeting the cholinergic system in lung tumors. Int J Oncol 29(6):1381–1388

    CAS  PubMed  Google Scholar 

  78. Berne S, Pohleven F, Turk T, Sepcic K (2008) Induction of fruiting in oyster mushroom (Pleurotus ostreatus) by polymeric 3-alkylpyridinium salts. Mycol Res 112(Pt 9):1085–1087

    Article  CAS  PubMed  Google Scholar 

  79. Elersek T, Kosi G, Turk T, Pohleven F, Sepcic K (2008) Influence of polymeric 3-alkylpyridinium salts from the marine sponge Reniera sarai on the growth of algae and wood decay fungi. Biofouling 24(2):137–143

    Article  CAS  PubMed  Google Scholar 

  80. Grandic M, Araoz R, Molgo J, Turk T, Sepcic K, Benoit E, Frangez R (2013) Toxicity of the synthetic polymeric 3-alkylpyridinium salt (APS3) is due to specific block of nicotinic acetylcholine receptors. Toxicology 303:25–33

    Article  CAS  PubMed  Google Scholar 

  81. Turk T, Frangez R, Sepcic K (2007) Mechanisms of toxicity of 3-alkylpyridinium polymers from marine sponge Reniera sarai. Marine drugs 5(4):157–167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Yamada T, McGeer PL (1990) Oligodendroglial microtubular masses: an abnormality observed in some human neurodegenerative diseases. Neurosci Lett 120(2):163–166

    Article  CAS  PubMed  Google Scholar 

  83. Nishimura M, Tomimoto H, Suenaga T, Namba Y, Ikeda K, Akiguchi I, Kimura J (1995) Immunocytochemical characterization of glial fibrillary tangles in Alzheimer’s disease brain. Am J Pathol 146(5):1052–1058

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. The Biochemical journal 256(1):283–290

    CAS  PubMed  Google Scholar 

  85. Cohen PT (1997) Novel protein serine/threonine phosphatases: variety is the spice of life. Trends Biochem Sci 22(7):245–251

    Article  CAS  PubMed  Google Scholar 

  86. Borthwick EB, Zeke T, Prescott AR, Cohen PT (2001) Nuclear localization of protein phosphatase 5 is dependent on the carboxy-terminal region. FEBS Lett 491(3):279–284

    Article  CAS  PubMed  Google Scholar 

  87. Malchiodi-Albedi F, Petrucci TC, Picconi B, Iosi F, Falchi M (1997) Protein phosphatase inhibitors induce modification of synapse structure and Tau hyperphosphorylation in cultured rat hippocampal neurons. J Neurosci Res 48(5):425–438

    Article  CAS  PubMed  Google Scholar 

  88. Kim D, Su J, Cotman CW (1999) Sequence of neurodegeneration and accumulation of phosphorylated Tau in cultured neurons after okadaic acid treatment. Brain Res 839(2):253–262

    Article  CAS  PubMed  Google Scholar 

  89. Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I (1998) The regulation of phosphorylation of Tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett 426(2):248–254

    Article  CAS  PubMed  Google Scholar 

  90. Furukawa K, Wang Y, Yao PJ, Fu W, Mattson MP, Itoyama Y, Onodera H, D’Souza I, Poorkaj PH, Bird TD, Schellenberg GD (2003) Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia Tau mutation. J Neurochem 87(2):427–436

    Article  CAS  PubMed  Google Scholar 

  91. Stoppelkamp S, Bell HS, Palacios-Filardo J, Shewan DA, Riedel G, Platt B (2011) In vitro modelling of Alzheimer’s disease: degeneration and cell death induced by viral delivery of amyloid and Tau. Exp Neurol 229(2):226–237

    Article  CAS  PubMed  Google Scholar 

  92. Zempel H, Mandelkow E (2014) Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci 37(12):721–732

    Article  CAS  PubMed  Google Scholar 

  93. Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA Tau transgenes. Neurobiology of disease 7(2):87–98

    Article  CAS  PubMed  Google Scholar 

  94. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of Tau in mice expressing normal human Tau isoforms. J Neurochem 86(3):582–590

    Article  CAS  PubMed  Google Scholar 

  95. Polydoro M, Acker CM, Duff K, Castillo PE, Davies P (2009) Age-dependent impairment of cognitive and synaptic function in the htau mouse model of Tau pathology. The Journal of neuroscience : the official journal of the Society for Neuroscience 29(34):10741–10749

    Article  CAS  Google Scholar 

  96. Khandelwal PJ, Dumanis SB, Herman AM, Rebeck GW, Moussa CE (2012) Wild type and P301L mutant Tau promote neuro-inflammation and alpha-Synuclein accumulation in lentiviral gene delivery models. Molecular and cellular neurosciences 49(1):44–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Dayton RD, Wang DB, Cain CD, Schrott LM, Ramirez JJ, King MA, Klein RL (2012) Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus. Exp Neurol 233(2):807–814

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Caillierez R, Begard S, Lecolle K, Deramecourt V, Zommer N, Dujardin S, Loyens A, Dufour N, Auregan G, Winderickx J, Hantraye P, Deglon N, Buee L, Colin M (2013) Lentiviral delivery of the human wild-type Tau protein mediates a slow and progressive neurodegenerative Tau pathology in the rat brain. Molecular therapy : the journal of the American Society of Gene Therapy 21(7):1358–1368

    Article  CAS  Google Scholar 

  99. Dujardin S, Lecolle K, Caillierez R, Begard S, Zommer N, Lachaud C, Carrier S, Dufour N, Auregan G, Winderickx J, Hantraye P, Deglon N, Colin M, Buee L (2014) Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism relevance to sporadic tauopathies. Acta Neuropathol Commun 2:14

    Article  PubMed Central  PubMed  Google Scholar 

  100. He J, Yamada K, Zou LB, Nabeshima T (2001) Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats. J Neural Transm Vienna Austria 108(12):1435–1443

    Article  CAS  Google Scholar 

  101. Sun L, Liu SY, Zhou XW, Wang XC, Liu R, Wang Q, Wang JZ (2003) Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced Tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience 118(4):1175–1182

    Article  CAS  PubMed  Google Scholar 

  102. He J, Yang Y, Xu H, Zhang X, Li XM (2005) Olanzapine attenuates the okadaic acid-induced spatial memory impairment and hippocampal cell death in rats. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 30(8):1511–1520

    Article  CAS  Google Scholar 

  103. Arendt T, Holzer M, Fruth R, Bruckner MK, Gartner U (1995) Paired helical filament-like phosphorylation of Tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. Neuroscience 69(3):691–698

    Article  CAS  PubMed  Google Scholar 

  104. Millward TA, Zolnierowicz S, Hemmings BA (1999) Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24(5):186–191

    Article  CAS  PubMed  Google Scholar 

  105. Herzig S, Neumann J (2000) Effects of serine/threonine protein phosphatases on ion channels in excitable membranes. Physiol Rev 80(1):173–210

    CAS  PubMed  Google Scholar 

  106. Zhang Z, Simpkins JW (2010) An okadaic acid-induced model of tauopathy and cognitive deficiency. Brain Res 1359:233–246

    Article  CAS  PubMed  Google Scholar 

  107. Khatoon S, Grundke-Iqbal I, Iqbal K (1992) Brain levels of microtubule-associated protein Tau are elevated in Alzheimer’s disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem 59(2):750–753

    Article  CAS  PubMed  Google Scholar 

  108. Khatoon S, Grundke-Iqbal I, Iqbal K (1994) Levels of normal and abnormally phosphorylated Tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett 351(1):80–84

    Article  CAS  PubMed  Google Scholar 

  109. Holzer M, Holzapfel HP, Zedlick D, Bruckner MK, Arendt T (1994) Abnormally phosphorylated Tau protein in Alzheimer’s disease: heterogeneity of individual regional distribution and relationship to clinical severity. Neuroscience 63(2):499–516

    Article  CAS  PubMed  Google Scholar 

  110. Thal DR, Holzer M, Rub U, Waldmann G, Gunzel S, Zedlick D, Schober R (2000) Alzheimer-related Tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp Neurol 163(1):98–110

    Article  CAS  PubMed  Google Scholar 

  111. Wang X, Zhu M, Hjorth E, Cortes-Toro V, Eyjolfsdottir H, Graff C, Nennesmo I, Palmblad J, Eriksdotter M, Sambamurti K, Fitzgerald JM, Serhan CN, Granholm AC, Schultzberg M (2015) Resolution of inflammation is altered in Alzheimer’s disease. Alzheimer’s Dement J Alzheimer’s Assoc 11(1):40–50

    Article  Google Scholar 

  112. Bancher C, Braak H, Fischer P, Jellinger KA (1993) Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer’s and Parkinson’s disease patients. Neurosci Lett 162(1–2):179–182

    Article  CAS  PubMed  Google Scholar 

  113. Freedman M, Oscar-Berman M (1989) Spatial and visual learning deficits in Alzheimer’s and Parkinson’s disease. Brain Cogn 11(1):114–126

    Article  CAS  PubMed  Google Scholar 

  114. Gold CA, Budson AE (2008) Memory loss in Alzheimer’s disease: implications for development of therapeutics. Expert Rev Neurother 8(12):1879–1891

    Article  PubMed Central  PubMed  Google Scholar 

  115. Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science (New York, NY) 313(5790):1093–1097

    Article  CAS  Google Scholar 

  116. Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R (2014) Engineering a memory with LTD and LTP. Nature 511(7509):348–352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, Laferla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421

    Article  CAS  PubMed  Google Scholar 

  118. Rosenmann H, Grigoriadis N, Eldar-Levy H, Avital A, Rozenstein L, Touloumi O, Behar L, Ben-Hur T, Avraham Y, Berry E, Segal M, Ginzburg I, Abramsky O (2008) A novel transgenic mouse expressing double mutant Tau driven by its natural promoter exhibits tauopathy characteristics. Exp Neurol 212(1):71–84

    Article  CAS  PubMed  Google Scholar 

  119. Lo AC, Iscru E, Blum D, Tesseur I, Callaerts-Vegh Z, Buee L, de Strooper B, Balschun D, D’Hooge R (2013) Amyloid and Tau neuropathology differentially affect prefrontal synaptic plasticity and cognitive performance in mouse models of Alzheimer’s disease. J Alzheimer’s Dis JAD 37(1):109–125

    CAS  PubMed  Google Scholar 

  120. Platt B, Drever B, Koss D, Stoppelkamp S, Jyoti A, Plano A, Utan A, Merrick G, Ryan D, Melis V, Wan H, Mingarelli M, Porcu E, Scrocchi L, Welch A, Riedel G (2011) Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1. PLoS One 6(11):e27068

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Ryan D, Koss D, Porcu E, Woodcock H, Robinson L, Platt B, Riedel G (2013) Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent. Cell Mol life Sci CMLS 70(14):2603–2619

    Article  CAS  PubMed  Google Scholar 

  122. Robinson L, Goonawardena AV, Pertwee RG, Hampson RE, Riedel G (2007) The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats. Br J Pharmacol 151(5):688–700

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Robinson L, Goonawardena AV, Pertwee R, Hampson RE, Platt B, Riedel G (2010) WIN55,212-2 induced deficits in spatial learning are mediated by cholinergic hypofunction. Behav Brain Res 208(2):584–592

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Houssen WE, Lu Z, Edrada-Ebel R, Chatzi C, Tucker SJ, Sepcic K, Turk T, Zovko A, Shen S, Mancini I, Scott RH, Jaspars M (2010) Chemical synthesis and biological activities of 3-alkyl pyridinium polymeric analogues of marine toxins. J Chem Biol 3(3):113–125

    Article  PubMed Central  PubMed  Google Scholar 

  125. Paxinos G, Watson C (2013) The Rat Brain in stereotaxic coordinates, 7th edn. Academic Press, London

    Google Scholar 

Download references

Acknowledgments

This work was supported by the Alzheimer Research Trust (now ARUK) to GR, RHS and BP, as well as grants from the National Science Centre to AG and GN, and by statutory funds from the Nencki Institute of Experimental Biology (Warsaw, Poland) and School of Medical Sciences of the University of Aberdeen (UK). We gratefully acknowledge the help of students involved in this project: Kanola David, Jonathan Jones, Risto Kylanpaa, David McClelland, Rhian Evans, Iona Beange and Sandra Brooks.

Author information

Author notes

  1. Lianne Robinson

    Present address: Behavioural Neuroscience Core Facility, Division of Neuroscience, University of Dundee, Dundee, UK

  2. Anna Gasiorowska

    Present address: Mossakowski Medical Research Centre, Warsaw, Poland

Authors and Affiliations

  1. School of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, UK

    Dave J. Koss, Lianne Robinson, Roderick H. Scott, Bettina Platt & Gernot Riedel

  2. Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland

    Anna Mietelska-Porowska, Anna Gasiorowska & Grazyna Niewiadomska

  3. Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia

    Kristina Sepčić & Tom Turk

  4. Department of Chemistry, Marine Biodiscovery Centre, University of Aberdeen, Aberdeen, UK

    Marcel Jaspars

Authors
  1. Dave J. Koss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lianne Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Mietelska-Porowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Gasiorowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristina Sepčić
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom Turk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcel Jaspars
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Grazyna Niewiadomska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roderick H. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bettina Platt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gernot Riedel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gernot Riedel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koss, D.J., Robinson, L., Mietelska-Porowska, A. et al. Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits. Cell. Mol. Life Sci. 72, 4613–4632 (2015). https://doi.org/10.1007/s00018-015-1949-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-1949-4

Keywords

Search

Navigation