Skip to main content

Advertisement

SpringerLink
Log in

First-in-Rat Study of Human Alzheimer’s Disease Tau Propagation

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

One of the key features of misfolded tau in human neurodegenerative disorders is its propagation from one brain area into many others. In the last decade, in vivo tau spreading has been replicated in several mouse transgenic models expressing mutated human tau as well as in normal non-transgenic mice. In this study, we demonstrate for the first time that insoluble tau isolated from human AD brain induces full-blown neurofibrillary pathology in a sporadic rat model of tauopathy expressing non-mutated truncated tau protein. By using specific monoclonal antibodies, we were able to monitor the spreading of tau isolated from human brain directly in the rat hippocampus. We found that exogenous human AD tau was able to spread from the area of injection and induce tau pathology. Interestingly, solubilisation of insoluble AD tau completely abolished the capability of tau protein to induce and spread of neurofibrillary pathology in the rat brain. Our results show that exogenous tau is able to induce and drive neurofibrillary pathology in rat model for human tauopathy in a similar way as it was described in various mouse transgenic models. Rat tau spreading model has many advantages over mouse and other organisms including size and complexity, and thus is highly suitable for identification of pathogenic mechanism of tau spreading.

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

Similar content being viewed by others

References

  1. Williams DR (2006) Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern Med J 36(10):652–660. https://doi.org/10.1111/j.1445-5994.2006.01153.x

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71(5):362–381. https://doi.org/10.1097/NEN.0b013e31825018f7

    Article  PubMed  Google Scholar 

  4. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N et al (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685–697. https://doi.org/10.1016/j.neuron.2011.11.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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:e31302. https://doi.org/10.1371/journal.pone.0031302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. https://doi.org/10.1038/ncb1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237. https://doi.org/10.1007/s00401-014-1373-0

    Article  CAS  PubMed  Google Scholar 

  8. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A 110:9535–9540. https://doi.org/10.1073/pnas.1301175110

    Article  PubMed  PubMed Central  Google Scholar 

  9. Novak M (1994) Truncated tau protein as a new marker for Alzheimer’s disease. Acta Virol 38:173–189

    CAS  PubMed  Google Scholar 

  10. Hu W, Zhang X, Tung YC, Xie S, Liu F, Iqbal K (2016) Hyperphosphorylation determines both the spread and the morphology of tau pathology. Alzheimers Dement 12(10):1066–1077. https://doi.org/10.1016/j.jalz.2016.01.014

    Article  PubMed  Google Scholar 

  11. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 33:1024–1037. https://doi.org/10.1523/JNEUROSCI.2642-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI (2012) Trans-cellular propagation of tau aggregation by fibrillar species. J Biol Chem 287:19440–19451. https://doi.org/10.1074/jbc.M112.346072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T, Neugebauer V, Jackson GR, Kayed R (2012) Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep 2:700. https://doi.org/10.1038/srep00700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M et al (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. https://doi.org/10.1016/j.nbd.2014.08.032

    Article  CAS  PubMed  Google Scholar 

  15. Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, Steinberg JI, Margittai M et al (2013) Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288:1856–1870. https://doi.org/10.1074/jbc.M112.394528

    Article  CAS  PubMed  Google Scholar 

  16. Levarska L, Zilka N, Jadhav S, Neradil P, Novak M (2013) Of rodents and men: the mysterious interneuronal pilgrimage of misfolded protein tau in Alzheimer’s disease. J Alzheimers Dis 37:569–577. https://doi.org/10.3233/JAD-131106

    Article  CAS  PubMed  Google Scholar 

  17. Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA et al (2014) A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 127:667–683. https://doi.org/10.1007/s00401-014-1254-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, Gathagan RJ, Iba M et al (2016) Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 213(12):2635–2654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Koson P, Zilka N, Kovac A, Kovacech B, Korenova M, Filipcik P, Novak M (2008) Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci 28:239–246. https://doi.org/10.1111/j.1460-9568.2008.06329.x

    Article  PubMed  Google Scholar 

  20. Greenberg SG, Davies PA (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A 87:5827–5831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jadhav S, Katina S, Kovac A, Kazmerova Z, Novak M, Zilka N (2015) Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front Cell Neurosci 9:24. https://doi.org/10.3389/fncel.2015.00024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roher AE, Palmer KC, Chau V, Ball MJ (1998) Isolation and chemical characterization of Alzheimer’s disease paired helical filament cytoskeletons: differentiation from amyloid plaque core protein. Js Cell Biol 107:2703–2716

    Article  Google Scholar 

  23. Zilka N, Kovacech B, Barath P, Kontsekova E, Novak M (2012) The self-perpetuating tau truncation circle. Biochem Soc Trans 40:681–686. https://doi.org/10.1042/BST20120015

    Article  CAS  PubMed  Google Scholar 

  24. Forest SK, Acker CM, d'Abramo C, Davies P (2013) Methods for measuring tau pathology in transgenic mouse models. J Alzheimers Dis 33:463–471. https://doi.org/10.3233/JAD-2012-121354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. Academic Press, Chicago

    Google Scholar 

  26. Soltys K, Rolkova G, Vechterova L, Filipcik P, Zilka N, Kontsekova E, Novak M (2005) First insert of tau protein is present in all stages of tau pathology in Alzheimer’s disease. Neuroreport 16:1677–1681

    Article  CAS  PubMed  Google Scholar 

  27. Smith MA, Siedlak SL, Richey PL, Nagaraj RH, Elhammer A, Perry G (1996) Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res 717:99–108

    Article  CAS  PubMed  Google Scholar 

  28. Yang LS, Gordon-Krajcer W, Ksiezak-Reding H (1997) Tau released from paired helical filaments with formic acid or guanidine is susceptible to calpain-mediated proteolysis. J Neurochem 69:1548–1558

    Article  CAS  PubMed  Google Scholar 

  29. Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, Owen C, Aldea P et al (2016) Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med 8(338):338ra66. https://doi.org/10.1126/scitranslmed.aaf2362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, Rawal B, Parisi JE et al (2015) Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain 138(Pt 5):1370–1381. https://doi.org/10.1093/brain/awv050

    Article  PubMed  PubMed Central  Google Scholar 

  31. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849. https://doi.org/10.1074/jbc.M111.277061

    Article  CAS  PubMed  Google Scholar 

  32. Calafate S, Buist A, Miskiewicz K, Vijayan V, Daneels G, de Strooper B, de Wit J, Verstreken P et al (2015) Synaptic contacts enhance cell-to-cell tau pathology propagation. Cell Rep 11:1176–1183. https://doi.org/10.1016/j.celrep.2015.04.043

    Article  CAS  PubMed  Google Scholar 

  33. Sokolow S, Henkins KM, Bilousova T, Gonzalez B, Vinters HV, Miller CA, Cornwell L, Poon WW et al (2015) Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer’s disease. J Neurochem 133:368–379. https://doi.org/10.1111/jnc.12991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chai X, Dage JL, Citron M (2012) Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis 48:356–366. https://doi.org/10.1016/j.nbd.2012.05.021

    Article  CAS  PubMed  Google Scholar 

  35. Clarke J, Thornell A, Corbett D, Soininen H, Hiltunen M, Jolkkonen J (2007) Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur J Neurosci 26(7):1845–1852

    Article  PubMed  Google Scholar 

  36. Agca C, Fritz JJ, Walker LC, Levey AI, Chan AW, Lah JJ, Agca Y (2008) Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer’s disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci 9:28

    Article  PubMed  PubMed Central  Google Scholar 

  37. Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F et al (2004) Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis 6(3):209–219

    Article  CAS  PubMed  Google Scholar 

  38. Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, Scott RW, Howland DS (2009) A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol Aging 30(7):1078–1090

    Article  CAS  PubMed  Google Scholar 

  39. Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D et al (2007) A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation. Biochem Biophys Res Commun 358(3):777–782

    Article  CAS  PubMed  Google Scholar 

  40. Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M et al (2008) A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31(1):46–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL (2004) Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 10(1–6):36–44

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Korhonen P, van Groen T, Thornell A, Kyrylenko S, Soininen ML, Ojala J, Peltomaa E, Tanila H et al (2011) Characterization of a novel transgenic rat carrying human tau with mutation P301L. Neurobiol Aging 32(12):2314–2315

    Article  CAS  PubMed  Google Scholar 

  43. 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 108:1167–1176. https://doi.org/10.1111/j.1471-4159.2009.05869.x

    Article  CAS  PubMed  Google Scholar 

  44. Chui HC (1987) The significance of clinically defined subgroups of Alzheimer’s disease. J Neural Transm Suppl 24:57–68

    CAS  PubMed  Google Scholar 

  45. Thalhauser CJ, Komarova NL (2012) Alzheimer’s disease: rapid and slow progression. J R Soc Interface 9(66):119–126. https://doi.org/10.1098/rsif.2011.0134

    Article  PubMed  Google Scholar 

  46. Andronesi OC, von Bergen M, Biernat J, Seidel K, Griesinger C, Mandelkow E, Baldus M (2008) Characterization of Alzheimer’s-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy. J Am Chem Soc 130:5922–5928. https://doi.org/10.1021/ja7100517

    Article  CAS  PubMed  Google Scholar 

  47. Ahmad F, Yadav D, Taneja S (1992) Determining stability of proteins from guanidinium chloride transition curves. Biochem J 287:481–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Camilloni C, Rocco AG, Eberini I, Gianazza E, Broglia RA, Tiana G (2008) Urea and guanidinium chloride denature protein L in different ways in molecular dynamics simulations. Biophys J 94:4654–4661. https://doi.org/10.1529/biophysj.107.125799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. England JL, Haran G (2011) Role of solvation effects in protein denaturation: from thermodynamics to single molecules and back. Annu Rev Phys Chem 62:257–277. https://doi.org/10.1146/annurev-physchem-032210-103531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O'Neill MJ et al (2015) Conformation determines the seeding potencies of native and recombinant tau aggregates. J Biol Chem 290(2):1049–1065. https://doi.org/10.1074/jbc.M114.589309

    Article  CAS  PubMed  Google Scholar 

  51. O’Brien E, Dima R, Brooks B, Thirumalai D (2007) Interactions between hydrophobic and ionic solutes in aqueous guanidinium chloride and urea solutions: lessons for protein denaturation mechanism. J Am Chem Soc 129:7346–7353. https://doi.org/10.1021/ja069232+

    Article  CAS  PubMed  Google Scholar 

  52. 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 531:538–542

    Article  CAS  PubMed  Google Scholar 

  53. Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella CV, Landi A, Szekeres PG et al (2016) Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci 36(3):762–772. https://doi.org/10.1523/JNEUROSCI.3542-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Smolek T, Jadhav S, Valachova B, Vogels T, Legath J, Novak P, Zilka N (2017) Transmission of tau pathology from human to rodent brain: How to humanise animal models for Alzheimer’s disease research. J Alzheimers Dis Parkinsonism 7:400. https://doi.org/10.4172/2161-0460.1000400

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank to the brain banks from Newcastle, London and Kuopio for providing the brain tissues.

Funding

The work is supported by research grants JPND ReFRAME, EU structural fund 26240220046, APVV-14-0872, VEGA 2/0164/16 and 2/0181/17, and Axon Neuroscience R&D Services SE.

Author information

Authors and Affiliations

  1. Institute of Neuroimmunology, Slovak Academy of Sciences, Centre of Excellence for Alzheimer’s Disease and Related Disorders, Dubravska 9, 845 10, Bratislava, Slovak Republic

    Tomas Smolek, Santosh Jadhav, Veronika Brezovakova, Veronika Cubinkova, Bernadeta Valachova, Petr Novak & Norbert Zilka

  2. Axon Neuroscience R&D Services SE, Dvořákovo nábrežie 10, Bratislava, Slovak Republic

    Tomas Smolek, Santosh Jadhav, Veronika Cubinkova & Norbert Zilka

  3. Axon Neuroscience CRM Services SE, Dvořákovo nábrežie 10, Bratislava, Slovak Republic

    Petr Novak

Authors
  1. Tomas Smolek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Santosh Jadhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Veronika Brezovakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Veronika Cubinkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernadeta Valachova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Petr Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norbert Zilka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norbert Zilka.

Ethics declarations

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Electronic supplementary material

Figure 1

Formation of neurofibrillary tangles in AD-tau injected animals is a dose dependent process. Immunomicrographs showing AT8 positive tangles after injection of 600 ng (a,d) or 400 ng (d-e) of AD-tau at both the injected (a-b) and non-injected side (d-e). Graphs showing number of AT8 positive tangles in injected side (c) or non‑injected side (f). Statistical analysis revealed significantly higher level of tangles after injection of 600 ng of AD-tau in injected site. Paired t-test, p values: *p < 0.05. (GIF 44 kb)

High resolution image (TIF 1757 kb)

Figure 2

Comparison of immunoblot and Ponceau for control of loading of insoluble tau extract. a. Immunoblotting of insoluble tau extracts isolated from control (Ctrl) and AD-tau injected (AD-tau 1,2,3) groups using pan-tau antibody DC25 shows higher levels of DC25 immuno-positivity in the AD-tau injected group. However, no change in protein levels is observed by ponceau staining (b). Sarkosyl insoluble tau extract from brainstem of transgenic rat model expressing human truncated tau (+ve) and PHF-tau were used as controls. (JPG 248 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smolek, T., Jadhav, S., Brezovakova, V. et al. First-in-Rat Study of Human Alzheimer’s Disease Tau Propagation. Mol Neurobiol 56, 621–631 (2019). https://doi.org/10.1007/s12035-018-1102-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1102-0

Keywords

Search

Navigation