Widespread tau seeding activity at early Braak stages

Jennifer L. Furman; Jaime Vaquer-Alicea; Charles L. White; Nigel J. Cairns; Peter T. Nelson; Marc I. Diamond

doi:10.1007/s00401-016-1644-z

Widespread tau seeding activity at early Braak stages

Jennifer L. Furman, Jaime Vaquer-Alicea, Charles L. White, Nigel J. Cairns, Peter T. Nelson, Marc I. Diamond

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	91-100
Number of pages	10
Journal	Acta Neuropathologica
Volume	133
Issue number	1
DOIs	https://doi.org/10.1007/s00401-016-1644-z
State	Published - Jan 1 2017

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.

Keywords

Alzheimer’s disease
Braak staging
Neuropathology
Propagation
Seeding
Tau

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00401-016-1644-z

Cite this

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title = "Widespread tau seeding activity at early Braak stages",

abstract = "Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer{\textquoteright}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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author = "Furman, {Jennifer L.} and Jaime Vaquer-Alicea and White, {Charles L.} and Cairns, {Nigel J.} and Nelson, {Peter T.} and Diamond, {Marc I.}",

note = "Funding Information: 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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg.",

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Widespread tau seeding activity at early Braak stages

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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