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Widespread tau seeding activity at early Braak stages - Acta Neuropathologica

  • ️Diamond, Marc I.
  • ️Tue Nov 22 2016

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.

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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).

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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

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  2. Jaime Vaquer-Alicea

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  3. Charles L. White III

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  4. Nigel J. Cairns

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  5. Peter T. Nelson

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Corresponding author

Correspondence to Marc I. Diamond.

Electronic supplementary material

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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

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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

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  • Received: 30 June 2016

  • Revised: 11 November 2016

  • Accepted: 12 November 2016

  • Published: 22 November 2016

  • Issue Date: January 2017

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

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