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.
Document Type
Article
Publication Date
1-2017
Digital Object Identifier (DOI)
https://doi.org/10.1007/s00401-016-1644-z
Funding Information
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).
Related Content
The online version of this article (doi: 10.1007/s00401-016-1644-z) contains supplementary material, which is available to authorized users.
Repository Citation
Furman, Jennifer L.; Vaquer-Alicea, Jaime; White, Charles L.; Cairns, Nigel J.; Nelson, Peter T.; and Diamond, Marc I., "Widespread Tau Seeding Activity at Early Braak Stages" (2017). Pathology and Laboratory Medicine Faculty Publications. 35.
https://uknowledge.uky.edu/pathology_facpub/35
Supplemental Figure 1.
401_2016_1644_MOESM2_ESM.pdf (263 kB)
Supplemental Figure 2.
Notes/Citation Information
Published in Acta Neuropathologica, v. 133, issue 1, p. 91-100.
© Springer-Verlag Berlin Heidelberg 2016
The copyright holder has granted the permission for posting the article here.
This is a post-peer-review, pre-copyedit version of an article published in Acta Neuropathologica. The final authenticated version is available online at: https://doi.org/10.1007/s00401-016-1644-z.