Acta Neuropathologica

, Volume 127, Issue 2, pp 257–270

Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model

  • Manuela Polydoro
  • Volodymyr I. Dzhala
  • Amy M. Pooler
  • Samantha B. Nicholls
  • A. Patrick McKinney
  • Laura Sanchez
  • Rose Pitstick
  • George A. Carlson
  • Kevin J. Staley
  • Tara L. Spires-Jones
  • Bradley T. Hyman
Original Paper

Abstract

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease, are intracellular silver and thioflavin S-staining aggregates that emerge from earlier accumulation of phospho-tau in the soma. Whether soluble misfolded but nonfibrillar tau disrupts neuronal function is unclear. Here we investigate if soluble pathological tau, specifically directed to the entorhinal cortex (EC), can cause behavioral or synaptic deficits. We studied rTgTauEC transgenic mice, in which P301L mutant human tau overexpressed primarily in the EC leads to the development of tau pathology, but only rare NFT at 16 months of age. We show that the early tau lesions are associated with nearly normal performance in contextual fear conditioning, a hippocampal-related behavior task, but more robust changes in neuronal system activation as marked by Arc induction and clear electrophysiological defects in perforant pathway synaptic plasticity. Electrophysiological changes were likely due to a presynaptic deficit and changes in probability of neurotransmitter release. The data presented here support the hypothesis that misfolded and hyperphosphorylated tau can impair neuronal function within the entorhinal-hippocampal network, even prior to frank NFT formation and overt neurodegeneration.

Keywords

Tau Arc induction Synaptic dysfunction Alzheimer’s disease 

Supplementary material

401_2013_1215_MOESM1_ESM.pptx (23.6 mb)
Supplementary material 1 (PPTX 24190 kb)
401_2013_1215_MOESM2_ESM.docx (22 kb)
Supplementary material 2 (DOCX 22 kb)

References

  1. 1.
    Bellone C, Luscher C (2005) mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur J Neurosci 21(5):1280–1288. doi:10.1111/j.1460-9568.2005.03979.x PubMedCrossRefGoogle Scholar
  2. 2.
    Bi M, Ittner A, Ke YD, Gotz J, Ittner LM (2011) Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS ONE 6(12):e26860. doi:10.1371/journal.pone.0026860 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739(2–3):216–223. doi:10.1016/j.bbadis.2004.08.014 PubMedCrossRefGoogle Scholar
  4. 4.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259PubMedCrossRefGoogle Scholar
  5. 5.
    Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271(51):32789–32795PubMedCrossRefGoogle Scholar
  6. 6.
    Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Sudhof TC (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA 101(41):14966–14971. doi:10.1073/pnas.0406283101 PubMedCrossRefGoogle Scholar
  7. 7.
    Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4(9):873–874. doi:10.1038/nn0901-873nn0901-873 PubMedCrossRefGoogle Scholar
  8. 8.
    Czerniawski J, Ree F, Chia C, Ramamoorthi K, Kumata Y, Otto TA (2011) The importance of having Arc: expression of the immediate-early gene Arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptor antagonism. J Neurosci 31(31):11200–11207. doi:10.1523/JNEUROSCI.2211-11.2011 PubMedCrossRefGoogle Scholar
  9. 9.
    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 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Debanne D, Guerineau NC, Gahwiler BH, Thompson SM (1996) Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release. J Physiol 491(Pt 1):163–176PubMedGoogle Scholar
  11. 11.
    Dittman JS, Regehr WG (1998) Calcium dependence and recovery kinetics of presynaptic depression at the climbing fiber to Purkinje cell synapse. J Neurosci 18(16):6147–6162PubMedGoogle Scholar
  12. 12.
    Ebert DH, Greenberg ME (2013) Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493(7432):327–337. doi:10.1038/nature11860 PubMedCrossRefGoogle Scholar
  13. 13.
    Elmqvist D, Quastel DM (1965) A quantitative study of end-plate potentials in isolated human muscle. J Physiol 178(3):505–529PubMedGoogle Scholar
  14. 14.
    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. doi:10.1097/NEN.0b013e318220a658 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Gallyas F (1971) Silver staining of Alzheimer’s neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung 19(1):1–8PubMedGoogle Scholar
  16. 16.
    Ghasemzadeh MB, Permenter LK, Lake R, Worley PF, Kalivas PW (2003) Homer1 proteins and AMPA receptors modulate cocaine-induced behavioural plasticity. Eur J Neurosci 18(6):1645–1651. doi:2880 PubMedCrossRefGoogle Scholar
  17. 17.
    Greenberg SG, Davies P, Schein JD, Binder LI (1992) Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. J Biol Chem 267(1):564–569PubMedGoogle Scholar
  18. 18.
    Harris JA, Koyama A, Maeda S, Ho K, Devidze N, Dubal DB, Yu GQ, Masliah E, Mucke L (2012) Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS ONE 7(9):e45881. doi:10.1371/journal.pone.0045881 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130(Pt 5):1386–1394. doi:10.1093/brain/awm065 PubMedCrossRefGoogle Scholar
  20. 20.
    Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225(4667):1168–1170PubMedCrossRefGoogle Scholar
  21. 21.
    Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62(6):925–931PubMedCrossRefGoogle Scholar
  22. 22.
    Jiang L, Sun S, Nedergaard M, Kang J (2000) Paired-pulse modulation at individual GABAergic synapses in rat hippocampus. J Physiol 523(Pt 2):425–439 PHY_0118 [pii]PubMedCrossRefGoogle Scholar
  23. 23.
    Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48(2):128–132. doi:10.1002/(SICI)1097-4547(19970415)48:2<128:AID-JNR5>3.0.CO;2-E PubMedCrossRefGoogle Scholar
  24. 24.
    Katz B, Miledi R (1968) The role of calcium in neuromuscular facilitation. J Physiol 195(2):481–492PubMedGoogle Scholar
  25. 25.
    Ke YD, Dramiga J, Schutz U, Kril JJ, Ittner LM, Schroder H, Gotz J (2012) Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer’s and Pick’s disease. PLoS ONE 7(4):e35678. doi:10.1371/journal.pone.0035678 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Kim JH, Vezina P (1998) Metabotropic glutamate receptors are necessary for sensitization by amphetamine. Neuro Report 9(3):403–406Google Scholar
  27. 27.
    Kirischuk S, Clements JD, Grantyn R (2002) Presynaptic and postsynaptic mechanisms underlie paired pulse depression at single GABAergic boutons in rat collicular cultures. J Physiol 543(Pt 1):99–116 PHY_021576 [pii]PubMedCrossRefGoogle Scholar
  28. 28.
    Kopeikina KJ, Carlson GA, Pitstick R, Ludvigson AE, Peters A, Luebke JI, Koffie RM, Frosch MP, Hyman BT, Spires-Jones TL (2011) Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer’s disease brain. Am J Pathol 179(4):2071–2082. doi:10.1016/j.ajpath.2011.07.004 PubMedCrossRefGoogle Scholar
  29. 29.
    Kopeikina KJ, Hyman BT, Spires-Jones TL (2012) Soluble forms of tau are toxic in Alzheimer’s disease. Trans Neurosci 3(3):223–233. doi:10.2478/s13380-012-0032-y CrossRefGoogle Scholar
  30. 30.
    Ksiezak-Reding H, Davies P, Yen SH (1988) Alz 50, a monoclonal antibody to Alzheimer’s disease antigen, cross-reacts with tau proteins from bovine and normal human brain. J Biol Chem 263(17):7943–7947PubMedGoogle Scholar
  31. 31.
    Kwon HB, Castillo PE (2008) Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. Neuron 57(1):108–120. doi:10.1016/j.neuron.2007.11.024 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lee D, Lee KH, Ho WK, Lee SH (2007) Target cell-specific involvement of presynaptic mitochondria in post-tetanic potentiation at hippocampal mossy fiber synapses. J Neurosci 27(50):13603–13613. doi:10.1523/JNEUROSCI.3985-07.2007 PubMedCrossRefGoogle Scholar
  33. 33.
    Lee JS, Kim MH, Ho WK, Lee SH (2008) Presynaptic release probability and readily releasable pool size are regulated by two independent mechanisms during posttetanic potentiation at the calyx of Held synapse. J Neurosci 28(32):7945–7953. doi:10.1523/JNEUROSCI.2165-08.2008 PubMedCrossRefGoogle Scholar
  34. 34.
    Lee SH, Kim MH, Lee JY, Lee D, Park KH, Ho WK (2007) Na +/Ca2 + exchange and Ca2 + homeostasis in axon terminals of mammalian central neurons. Ann N Y Acad Sci 1099:396–412. doi:1099/1/39610.1196/annals.1387.011 PubMedCrossRefGoogle Scholar
  35. 35.
    Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7(2):e31302. doi:10.1371/journal.pone.0031302 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Manabe T, Wyllie DJ, Perkel DJ, Nicoll RA (1993) Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. J Neurophysiol 70(4):1451–1459PubMedGoogle Scholar
  37. 37.
    Mennerick S, Zorumski CF (1995) Presynaptic influence on the time course of fast excitatory synaptic currents in cultured hippocampal cells. J Neurosci 15(4):3178–3192PubMedGoogle Scholar
  38. 38.
    O’Donovan MJ, Rinzel J (1997) Synaptic depression: a dynamic regulator of synaptic communication with varied functional roles. Trends Neurosci 20(10):431–433 S0166-2236(97)01124-7 [pii]PubMedCrossRefGoogle Scholar
  39. 39.
    Otvos L Jr, Feiner L, Lang E, Szendrei GI, Goedert M, Lee VM (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res 39(6):669–673. doi:10.1002/jnr.490390607 PubMedCrossRefGoogle Scholar
  40. 40.
    Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bosl MR, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52(3):437–444. doi:10.1016/j.neuron.2006.08.024 PubMedCrossRefGoogle Scholar
  41. 41.
    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. J Neurosci 29(34):10741–10749. doi:10.1523/JNEUROSCI.1065-09.2009 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP (2013) Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep 14(4):389–394. doi:10.1038/embor.2013.15 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Prescott SA (1998) Interactions between depression and facilitation within neural networks: updating the dual-process theory of plasticity. Learn Mem 5(6):446–466PubMedGoogle Scholar
  44. 44.
    Quintanilla RA, Matthews-Roberson TA, Dolan PJ, Johnson GV (2009) Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease. J Biol Chem 284(28):18754–18766. doi:10.1074/jbc.M808908200 PubMedCrossRefGoogle Scholar
  45. 45.
    Rocher AB, Crimins JL, Amatrudo JM, Kinson MS, Todd-Brown MA, Lewis J, Luebke JI (2010) Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol 223(2):385–393. doi:10.1016/j.expneurol.2009.07.029 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Sakaba T, Neher E (2001) Quantitative relationship between transmitter release and calcium current at the calyx of held synapse. J Neurosci 21(2):462–476. doi:21/2/462 PubMedGoogle Scholar
  47. 47.
    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. Science 309(5733):476–481. doi:10.1126/science.1113694 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Stevens CF, Tsujimoto T (1995) Estimates for the pool size of releasable quanta at a single central synapse and for the time required to refill the pool. Proc Natl Acad Sci USA 92(3):846–849PubMedCrossRefGoogle Scholar
  49. 49.
    Stevens CF, Wesseling JF (1998) Activity-dependent modulation of the rate at which synaptic vesicles become available to undergo exocytosis. Neuron 21(2):415–424 S0896-6273(00)80550-4 [pii]PubMedCrossRefGoogle Scholar
  50. 50.
    Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis 20(Suppl 2):S265–S279. doi:10.3233/JAD-2010-100339 PubMedGoogle Scholar
  51. 51.
    Szumlinski KK, Toda S, Middaugh LD, Worley PF, Kalivas PW (2003) Evidence for a relationship between Group 1 mGluR hypofunction and increased cocaine and ethanol sensitivity in Homer2 null mutant mice. Ann N Y Acad Sci 1003:468–471PubMedCrossRefGoogle Scholar
  52. 52.
    Tagawa Y, Kanold PO, Majdan M, Shatz CJ (2005) Multiple periods of functional ocular dominance plasticity in mouse visual cortex. Nat Neurosci 8(3):380–388. doi:10.1038/nn1410 PubMedCrossRefGoogle Scholar
  53. 53.
    Thomson AM (2000) Facilitation, augmentation and potentiation at central synapses. Trends Neurosci 23(7):305–312 S0166-2236(00)01580-0 [pii]PubMedCrossRefGoogle Scholar
  54. 54.
    Van Hoesen GW, Pandya DN, Butters N (1972) Cortical afferents to the entorhinal cortex of the Rhesus monkey. Science 175(4029):1471–1473PubMedCrossRefGoogle Scholar
  55. 55.
    Wang LY, Kaczmarek LK (1998) High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394(6691):384–388. doi:10.1038/28645 PubMedCrossRefGoogle Scholar
  56. 56.
    Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM (2007) Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci USA 104(24):10252–10257. doi:10.1073/pnas.0703676104 PubMedCrossRefGoogle Scholar
  57. 57.
    Weaver CL, Espinoza M, Kress Y, Davies P (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21(5):719–727 S0197-4580(00)00157-3 [pii]PubMedCrossRefGoogle Scholar
  58. 58.
    Wilcox KS, Dichter MA (1994) Paired pulse depression in cultured hippocampal neurons is due to a presynaptic mechanism independent of GABAB autoreceptor activation. J Neurosci 14(3 Pt 2):1775–1788PubMedGoogle Scholar
  59. 59.
    Xiong ZQ, Stringer JL (1997) Effects of felbamate, gabapentin and lamotrigine on seizure parameters and excitability in the rat hippocampus. Epilepsy Res 27(3):187–194 S0920-1211(97)00022-3 [pii]PubMedCrossRefGoogle Scholar
  60. 60.
    Xu J, He L, Wu LG (2007) Role of Ca(2+) channels in short-term synaptic plasticity. Curr Opin Neurobiol 17(3):352–359. doi:10.1016/j.conb.2007.04.005 PubMedCrossRefGoogle Scholar
  61. 61.
    Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31(37):13110–13117. doi:10.1523/JNEUROSCI.2569-11.2011 PubMedCrossRefGoogle Scholar
  62. 62.
    Yasuda M, Mayford MR (2006) CaMKII activation in the entorhinal cortex disrupts previously encoded spatial memory. Neuron 50(2):309–318. doi:10.1016/j.neuron.2006.03.035 PubMedCrossRefGoogle Scholar
  63. 63.
    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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Manuela Polydoro
    • 1
  • Volodymyr I. Dzhala
    • 1
  • Amy M. Pooler
    • 1
    • 2
  • Samantha B. Nicholls
    • 1
  • A. Patrick McKinney
    • 3
  • Laura Sanchez
    • 1
  • Rose Pitstick
    • 4
  • George A. Carlson
    • 4
  • Kevin J. Staley
    • 1
  • Tara L. Spires-Jones
    • 1
  • Bradley T. Hyman
    • 1
  1. 1.Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA
  2. 2.Department of Neuroscience, Institute of PsychiatryKing’s College LondonLondonUK
  3. 3.NeuroBehavior Laboratory CoreHarvard NeuroDiscovery CenterBostonUSA
  4. 4.McLaughlin Research InstituteGreat FallsUSA

Personalised recommendations