4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration
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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.
KeywordsTau Progressive supranuclear palsy Corticobasal degeneration Strain Diagnosis Biomarker
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.
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.
- 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
- 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
- 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.Caughey B, Raymond GJ, Bessen RA (1998) Strain-dependent differences in beta-sheet conformations of abnormal prion protein. JBiolChem 273:32230–32235Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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