Skip to main content

Advertisement

SpringerLink
Log in

Widespread tau seeding activity at early Braak stages

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer’s disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also develop seeding activity prior to accumulation of phospho-tau. We measured tau seeding activity across four brain regions (hippocampus, frontal lobe, parietal lobe, and cerebellum) in 104 fresh-frozen human AD brain samples from all Braak stages. We observed widespread seeding activity, notably in regions predicted to be free of phospho-tau deposition, and in detergent-insoluble fractions that lacked tau detectable by ELISA. Seeding activity correlated positively with Braak stage and negatively with MMSE. Our results are consistent with early transcellular propagation of tau seeds that triggers subsequent development of neuropathology. The FRET-based seeding assay may also complement standard neuropathological classification of tauopathies.

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

Similar content being viewed by others

References

  1. Acker CM, Forest SK, Zinkowski R, Davies P, d’Abramo C (2013) Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. Neurobiol Aging 34:338–350. doi:10.1016/j.neurobiolaging.2012.05.010

    Article  CAS  PubMed  Google Scholar 

  2. Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S 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. doi:10.1007/s00401-014-1254-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639

    Article  CAS  PubMed  Google Scholar 

  4. 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. doi:10.1007/s00401-014-1373-0

    Article  CAS  PubMed  Google Scholar 

  5. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. doi:10.1007/s00401-006-0127-z

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278 (discussion 278–284)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O’Neill MJ et al (2011) Passive immunization with anti-tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J Biol Chem 286:34457–34467. doi:10.1074/jbc.M111.229633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz David H, Kopeikina Kathy J, Pitstick R, Sahara N, Ashe Karen H, Carlson George A et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fritschi SK, Cintron A, Ye L, Mahler J, Buhler A, Baumann F, Neumann M, Nilsson KP, Hammarstrom P, Walker LC et al (2014) Abeta seeds resist inactivation by formaldehyde. Acta Neuropathol 128:477–484. doi:10.1007/s00401-014-1339-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Frost B, Diamond MI (2009) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159

    PubMed  PubMed Central  Google Scholar 

  15. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Furman JL, Holmes BB, Diamond MI (2015) Sensitive detection of proteopathic seeding activity with FRET flow cytometry. J Vis Exp JoVE. doi:10.3791/53205

    PubMed  Google Scholar 

  17. Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB (1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20:573–579

    Article  CAS  PubMed  Google Scholar 

  18. Guo JL, Lee VMY (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. doi:10.1074/jbc.M110.209296

    Google Scholar 

  19. Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP et al (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA 110:E3138–E3147. doi:10.1073/pnas.1301440110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA. doi:10.1073/pnas.1411649111

    Google Scholar 

  21. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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. doi:10.1523/JNEUROSCI.2642-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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. doi:10.1074/jbc.M112.346072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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. doi:10.1371/journal.pone.0031302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI (2015) Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J Biol Chem 290:14893–14903. doi:10.1074/jbc.M115.652693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E 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. doi:10.1016/j.nbd.2014.08.032

    Article  CAS  PubMed  Google Scholar 

  27. 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 29:10741–10749. doi:10.1523/JNEUROSCI.1065-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Prusiner SB (1984) Some speculations about prions, amyloid, and Alzheimer’s disease. N Engl J Med 310:661–663. doi:10.1056/NEJM198403083101021

    Article  CAS  PubMed  Google Scholar 

  29. Raj A, Kuceyeski A, Weiner M (2012) A network diffusion model of disease progression in dementia. Neuron 73:1204–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. doi:10.1016/j.neuron.2014.04.047

    PubMed  PubMed Central  Google Scholar 

  31. Sanders DW, Kaufman SK, Holmes BB, Diamond MI (2016) Prions and protein assemblies that convey biological information in health and disease. Neuron 89:433–448. doi:10.1016/j.neuron.2016.01.026

    Article  CAS  PubMed  Google Scholar 

  32. Schweighauser M, Bacioglu M, Fritschi SK, Shimshek DR, Kahle PJ, Eisele YS, Jucker M (2015) Formaldehyde-fixed brain tissue from spontaneously ill alpha-synuclein transgenic mice induces fatal alpha-synucleinopathy in transgenic hosts. Acta Neuropathol 129:157–159. doi:10.1007/s00401-014-1360-5

    Article  PubMed  Google Scholar 

  33. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD (2009) Neurodegenerative diseases target large-scale human brain networks. Neuron 62:42–52. doi:10.1016/j.neuron.2009.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Small SA, Duff K (2008) Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60:534–542. doi:10.1016/j.neuron.2008.11.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stancu IC, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E, Buist A, Terwel D, Baatsen P, Oyelami T et al (2015) Templated misfolding of tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in tau transgenic mice. Acta Neuropathol 129:875–894. doi:10.1007/s00401-015-1413-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 21:719–727

    Article  CAS  PubMed  Google Scholar 

  37. 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 80:402–414. doi:10.1016/j.neuron.2013.07.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 53:337–351. doi:10.1016/j.neuron.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  39. Zhou J, Gennatas Efstathios D, Kramer Joel H, Miller Bruce L, Seeley William W (2012) Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73:1216–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Peter Davies for generously providing antibody reagents and ELISA protocol guidance. We thank the University of Texas, Southwestern Medical Center Alzheimer Disease Center, Washington University in St. Louis, the Sanders-Brown Center on Aging at the University of Kentucky, and Dr. Carol Tamminga in the Psychiatry Department at UT Southwestern Medical Center for providing pathological samples and corresponding clinical data. Ping Shang, HT(ASCP)QIHC, performed the immunohistochemical staining on tissue sections used in the Supp. Figure 1 illustrations, and Chan Foong, M.S., prepared the whole slide scanning images. Studies were supported by the Tau Consortium (to M.I.D), Coins for Alzheimer’s Research Trust (to N.J.C), and NIH grants awarded to M.I.D. (R01AG048678), J.L.F. (1F32NS087805), C.L.W. (AG12300), N.J.C. (P50 AG005681 and P01 AG003991) and P.T.N. (AG028383).

Author information

Authors and Affiliations

  1. Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NL10.120, Dallas, TX, 75390, USA

    Marc I. Diamond

  2. Department of Pathology, Southwestern Medical Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Charles L. White III

  3. Department of Neurology, Washington University, St. Louis, MO, USA

    Nigel J. Cairns

  4. Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Peter T. Nelson

  5. Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Jennifer L. Furman & Jaime Vaquer-Alicea

Authors
  1. Jennifer L. Furman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaime Vaquer-Alicea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles L. White III
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nigel J. Cairns
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter T. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marc I. Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc I. Diamond.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2016_1644_MOESM1_ESM.pdf

Supplemental Figure 1. Representative AT8 Staining of B1, B2, and B3 subjects. Hippocampus, frontal lobe, parietal lobe, and cerebellum stained with AT8 from representative subjects diagnosed as B1 (a-d), B2 (e-h), or B3 (i-l). Note that positive signal is restricted to entorhinal cortex (EC) in B1, spreads to hippocampus in B2, and to cortical regions in B3. Scale bar, 3 mm

401_2016_1644_MOESM2_ESM.pdf

Supplemental Figure 2. Representative cells with and without inclusions after transduction by tau seeds or control. Tau-CFP/YFP cells were transduced with empty liposomes (a), total (b, d, f, h, j) or insoluble (c, e, g, i, k) fractions. Variable degrees of aggregation were detectable with confocal microscopy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Furman, J.L., Vaquer-Alicea, J., White, C.L. et al. Widespread tau seeding activity at early Braak stages. Acta Neuropathol 133, 91–100 (2017). https://doi.org/10.1007/s00401-016-1644-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-016-1644-z

Keywords

Search

Navigation