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Acta Neuropathol. 2017 Jan;133(1):91-100. doi: 10.1007/s00401-016-1644-z. Epub 2016 Nov 22.

Widespread tau seeding activity at early Braak stages.

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Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Pathology, Southwestern Medical Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Neurology, Washington University, St. Louis, MO, USA.
Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NL10.120, Dallas, TX, 75390, USA.


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.


Alzheimer’s disease; Braak staging; Neuropathology; Propagation; Seeding; Tau

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