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4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

  • Eri Saijo
  • Michael A. MetrickII
  • Shunsuke Koga
  • Piero Parchi
  • Irene Litvan
  • Salvatore Spina
  • Adam Boxer
  • Julio C. Rojas
  • Douglas Galasko
  • Allison Kraus
  • Marcello Rossi
  • Kathy Newell
  • Gianluigi Zanusso
  • Lea T. Grinberg
  • William W. Seeley
  • Bernardino Ghetti
  • Dennis W. Dickson
  • Byron CaugheyEmail author
Original Paper

Abstract

To address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 106–109-fold dilutions of 4R tauopathy brain tissue but was orders of magnitude less responsive to brain with other types of tauopathy, such as from Alzheimer’s disease cases. The analytical sensitivity for synthetic 4R tau fibrils was ~ 50 fM or 2 fg/sample. A novel dimension of this tau RT-QuIC testing was the identification of three disease-associated classes of 4R tau seeds; these classes were revealed by conformational variations in the in vitro amplified tau fibrils as detected by thioflavin T fluorescence amplitudes and FTIR spectroscopy. Tau seeds were detected in postmortem cerebrospinal fluid (CSF) from all neuropathologically confirmed PSP and CBD cases but not in controls. CSF from living subjects had weaker seeding activities; however, mean assay responses for cases clinically diagnosed as PSP and CBD/corticobasal syndrome were significantly higher than those from control cases. Altogether, 4R RT-QuIC provides a practical cell-free method of detecting and subtyping pathologic 4R tau aggregates as biomarkers.

Keywords

Tau Progressive supranuclear palsy Corticobasal degeneration Strain Diagnosis Biomarker 

Notes

Acknowledgements

We thank David Dorward and Cindi Schwartz of the NIAID Research Technology Branch for help with electron microscopy. We thank Drs. Suzette Priola, Ankit Srivastava, and Bradley Groveman for helpful internal review of the initial manuscript. This work was supported in part by the Intramural Research Program of the NIAID. MM is supported by the NIH/Cambridge Scholars program. B. G. was supported by a grant of the US National Institutes of Health (P30AG010133) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine. D. G. is supported by NIH grant AGO5131 and the Shiley-Marcos Alzheimer’s Disease Research Center at UCSD. S. K. was supported by a research grant from the CBD Solutions. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer’s Disease Research Center (P50 AG005134). We also acknowledge the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine. Human tissue was obtained from the NIH NeuroBioBank. The UCSF Neurodegenerative Disease Brain Bank is supported by NIH Grants AG023501 and AG019724, the Tau Consortium, and the Bluefield Project to Cure FTD. LTG is funded by NIH K24053435. This study is also supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Grant No. ZIA AI001086-08). SS is funded by NIH K08 AG052648.

Author contributions

ES and BC conceived the overall project. ES and MAM designed, performed, and interpreted the primary experiments. ES developed the 4R RT-QuIC assays for brain and CSF. MAM helped to optimize the assay for brain tissue. MAM developed and performed the ATR-FTIR-based tau conformer subtyping. SK, PP, IL, SS, AB, MR, KN, GZ, LTG, WWS, BG, DG, and DWD provided tissue and/or fluid specimens and key clinical and neuropathological information, insights, and interpretations. AK, ES, MAM, and BC performed and/or interpreted electron microscopy analyses. ES, MAM, and BC prepared the manuscript. All authors helped to interpret the results and edit the manuscript.

Supplementary material

401_2019_2080_MOESM1_ESM.pdf (2.9 mb)
Supplementary material 1 (PDF 2921 kb)

References

  1. 1.
    Alster P, Nieciecki M, Koziorowski DM, Cacko A, Charzynska I, Krolicki L et al (2019) Thalamic and cerebellar hypoperfusion in single photon emission computed tomography may differentiate multiple system atrophy and progressive supranuclear palsy. Medicine (Baltimore) 98:e16603.  https://doi.org/10.1097/MD.0000000000016603 CrossRefGoogle Scholar
  2. 2.
    Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D et al (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 17:175–178.  https://doi.org/10.1038/nm.2294 CrossRefPubMedGoogle Scholar
  3. 3.
    Baron GS, Hughson AG, Raymond GJ, Offerdahl DK, Barton KA, Raymond LD et al (2011) Effect of glycans and the glycophosphatidylinositol anchor on strain dependent conformations of scrapie prion protein: improved purifications and infrared spectra. Biochemistry 50:4479–4490.  https://doi.org/10.1021/bi2003907 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT Jr, Caughey B (1995) Nongenetic propagation of strain-specific phenotypes of scrapie prion protein. Nature 375:698–700CrossRefGoogle Scholar
  5. 5.
    Bongianni M, Orrù CD, Groveman BR, Sacchetto L, Fiorini M, Tonoli G et al (2017) Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples. JAMA Neurol 74:1–8.  https://doi.org/10.1001/jamaneurol.2016.4614 CrossRefGoogle Scholar
  6. 6.
    Caughey B, Raymond GJ, Bessen RA (1998) Strain-dependent differences in beta-sheet conformations of abnormal prion protein. JBiolChem 273:32230–32235Google Scholar
  7. 7.
    Chung DC, Carlomagno Y, Cook CN, Jansen-West K, Daughrity L, Lewis-Tuffin LJ et al (2019) Tau exhibits unique seeding properties in globular glial tauopathy. Acta Neuropathol Commun 7:36.  https://doi.org/10.1186/s40478-019-0691-9 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dinkel PD, Siddiqua A, Huynh H, Shah M, Margittai M (2011) Variations in filament conformation dictate seeding barrier between three- and four-repeat tau. Biochemistry 50:4330–4336.  https://doi.org/10.1021/bi2004685 CrossRefPubMedGoogle Scholar
  9. 9.
    Drachman DA, Newell KL, Scully RE, Mark EJ, McNeely WF, Ebeling SH et al (1999) A 67-year-old man with three years of dementia—multisystem neurodegenerative disease (characterized by neurofibrillary changes and few plaques), findings consistent with dementia pugilistica. New Engl J Med 340:1269–1277.  https://doi.org/10.1056/Nejm199904223401609 CrossRefGoogle Scholar
  10. 10.
    Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S et al (2016) Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol 3:812–818.  https://doi.org/10.1002/acn3.338 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R et al (2018) Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561:137–140.  https://doi.org/10.1038/s41586-018-0454-y CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R et al (2019) Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568:420–423.  https://doi.org/10.1038/s41586-019-1026-5 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ et al (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190.  https://doi.org/10.1038/nature23002 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Foutz A, Appleby BS, Hamlin C, Liu X, Yang S, Cohen Y et al (2017) Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 81:79–92.  https://doi.org/10.1002/ana.24833 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Friedhoff P, Schneider A, Mandelkow EM, Mandelkow E (1998) Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. Biochemistry 37:10223–10230.  https://doi.org/10.1021/bi980537d CrossRefPubMedGoogle Scholar
  16. 16.
    Friedhoff P, von Bergen M, Mandelkow EM, Davies P, Mandelkow E (1998) A nucleated assembly mechanism of Alzheimer paired helical filaments. Proc Natl Acad Sci USA 95:15712–15717CrossRefGoogle Scholar
  17. 17.
    Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M (2015) Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 41:24–46.  https://doi.org/10.1111/nan.12213 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gibbons GS, Lee VMY, Trojanowski JQ (2019) Mechanisms of cell-to-cell transmission of pathological tau: a review. JAMA Neurol 76:101–108.  https://doi.org/10.1001/jamaneurol.2018.2505 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210.  https://doi.org/10.1146/annurev-neuro-072116-031153 CrossRefPubMedGoogle Scholar
  20. 20.
    Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168CrossRefGoogle Scholar
  21. 21.
    Greene P (2019) Progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. Continuum (Minneap Minn) 25:919–935.  https://doi.org/10.1212/CON.0000000000000751 CrossRefGoogle Scholar
  22. 22.
    Groveman BR, Dolan MA, Taubner LM, Kraus A, Wickner RB, Caughey B (2014) Parallel in-register intermolecular beta-sheet architectures for prion-seeded prion protein (PrP) amyloids. J Biol Chem 289:24129–24142.  https://doi.org/10.1074/jbc.M114.578344 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Groveman BR, Orru CD, Hughson AG, Raymond LD, Zanusso G, Ghetti B et al (2018) Rapid and ultra-sensitive quantitation of disease-associated alpha-synuclein seeds in brain and cerebrospinal fluid by alphaSyn RT-QuIC. Acta Neuropathol Commun 6:7.  https://doi.org/10.1186/s40478-018-0508-2 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331.  https://doi.org/10.1074/jbc.M110.209296 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796–812.  https://doi.org/10.1016/j.neuron.2016.09.055 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kraus A, Saijo E, Metrick MAI, Newell K, Sigurdson C, Zanusso G et al (2019) Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease. Acta Neuropathol 137:585–598.  https://doi.org/10.1007/s00401-018-1947-3 CrossRefPubMedGoogle Scholar
  27. 27.
    Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS et al (1996) Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 55:97–105.  https://doi.org/10.1097/00005072-199601000-00010 CrossRefPubMedGoogle Scholar
  28. 28.
    McGuire LI, Peden AH, Orru CD, Wilham JM, Appleford NE, Mallinson G et al (2012) RT-QuIC analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol 72:278–285CrossRefGoogle Scholar
  29. 29.
    Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X et al (2018) Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife.  https://doi.org/10.7554/eLife.36584 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW et al (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530–539.  https://doi.org/10.1056/NEJMoa1404401 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV et al (2017) Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci 37:11406–11423.  https://doi.org/10.1523/JNEUROSCI.1230-17.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR et al (2014) A test for Creutzfeldt-Jakob disease using nasal brushings. New Engl J Med 371:519–529CrossRefGoogle Scholar
  33. 33.
    Orru CD, Groveman BR, Hughson AG, Zanusso G, Coulthart MB, Caughey B (2015) Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. MBio.  https://doi.org/10.1128/mBio.02451-14 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Orru CD, Soldau K, Cordano C, Llibre-Guerra J, Green AJ, Sanchez H et al (2018) Prion seeds distribute throughout the eyes of sporadic Creutzfeldt-Jakob disease patients. MBio.  https://doi.org/10.1128/mBio.02095-18 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Orru CD, Yuan J, Appleby BS, Li B, Li Y, Winner D et al (2017) Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med.  https://doi.org/10.1126/scitranslmed.aam7785 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Redaelli V, Bistaffa E, Zanusso G, Salzano G, Sacchetto L, Rossi M et al (2017) Detection of prion seeding activity in the olfactory mucosa of patients with fatal familial insomnia. Sci Rep 7:46269.  https://doi.org/10.1038/srep46269 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI et al (2017) Ultrasensitive and selective detection of three-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. Acta Neuropathol 133:751–765.  https://doi.org/10.1007/s00401-017-1692-z CrossRefPubMedGoogle Scholar
  38. 38.
    Saijo E, Groveman BR, Kraus A, Metrick M, Orru CD, Hughson AG et al (2019) Ultrasensitive RT-QuIC seed amplification assays for disease-associated tau, alpha-synuclein, and prion aggregates. Methods Mol Biol 1873:19–37.  https://doi.org/10.1007/978-1-4939-8820-4_2 CrossRefPubMedGoogle Scholar
  39. 39.
    Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C (2014) Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Rep 7:261–268.  https://doi.org/10.1016/j.celrep.2014.02.031 CrossRefPubMedGoogle Scholar
  40. 40.
    Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288.  https://doi.org/10.1016/j.neuron.2014.04.047 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C et al (2017) Development of a biochemical diagnosis of parkinson disease by detection of alpha-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 74:163–172.  https://doi.org/10.1001/jamaneurol.2016.4547 CrossRefPubMedGoogle Scholar
  42. 42.
    Sharma AM, Thomas TL, Woodard DR, Kashmer OM, Diamond MI (2018) Tau monomer encodes strains. Elife.  https://doi.org/10.7554/eLife.37813 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA 94:4113–4118CrossRefGoogle Scholar
  44. 44.
    Takeda S, Commins C, DeVos SL, Nobuhara CK, Wegmann S, Roe AD et al (2016) Seed-competent HMW tau species accumulates in the cerebrospinal fluid of Alzheimer’s disease mouse model and human patients. Ann Neurol.  https://doi.org/10.1002/ana.24716 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082CrossRefGoogle Scholar
  46. 46.
    Tucker KL, Meyer M, Barde YA (2001) Neurotrophins are required for nerve growth during development. Nat Neurosci 4:29–37.  https://doi.org/10.1038/82868 CrossRefPubMedGoogle Scholar
  47. 47.
    von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM et al (2001) Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem.  https://doi.org/10.1074/jbc.M105196200 CrossRefGoogle Scholar
  48. 48.
    Wickner RB, Edskes HK, Gorkovskiy A, Bezsonov EE, Stroobant EE (2016) Yeast and fungal prions: amyloid-handling systems, amyloid structure, and prion biology. Adv Genet 93:191–236.  https://doi.org/10.1016/bs.adgen.2015.12.003 CrossRefPubMedGoogle Scholar
  49. 49.
    Wilham JM, Orrú CD, Bessen RA, Atarashi R, Sano K, Race B et al (2010) Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Path 6:e1001217.  https://doi.org/10.1371/journal.ppat.1001217 CrossRefGoogle Scholar
  50. 50.
    Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT et al (2016) Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci USA 113:E8187–E8196.  https://doi.org/10.1073/pnas.1616344113 CrossRefPubMedGoogle Scholar
  51. 51.
    Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K et al (2002) Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 51:730–739.  https://doi.org/10.1002/ana.10222 CrossRefPubMedGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Eri Saijo
    • 1
  • Michael A. MetrickII
    • 1
  • Shunsuke Koga
    • 2
  • Piero Parchi
    • 3
    • 4
  • Irene Litvan
    • 5
  • Salvatore Spina
    • 6
  • Adam Boxer
    • 6
  • Julio C. Rojas
    • 6
  • Douglas Galasko
    • 7
  • Allison Kraus
    • 1
  • Marcello Rossi
    • 3
  • Kathy Newell
    • 8
  • Gianluigi Zanusso
    • 9
  • Lea T. Grinberg
    • 6
    • 10
  • William W. Seeley
    • 6
  • Bernardino Ghetti
    • 8
  • Dennis W. Dickson
    • 2
  • Byron Caughey
    • 1
    Email author
  1. 1.LPVD, Rocky Mountain LaboratoriesNIAID, NIHHamiltonUSA
  2. 2.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  3. 3.IRCCS Istituto delle Scienze Neurologiche di BolognaBolognaItaly
  4. 4.Department of Experimental Diagnostic and Specialty Medicine (DIMES)University of BolognaBolognaItaly
  5. 5.Department of Neurosciences, Parkinson and Other Movement Disorders CenterUniversity of CaliforniaSan DiegoUSA
  6. 6.Memory and Aging Center, Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  7. 7.Department of NeurosciencesUniversity of CaliforniaSan DiegoUSA
  8. 8.Indiana University School of MedicineIndianapolisUSA
  9. 9.University of VeronaVeronaItaly
  10. 10.Department of Pathology, LIM-22University of Sao PauloSao PauloBrazil

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