title: Widespread tau seeding activity at early Braak stages.
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.
authors.affiliation: Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Furman
authors.affiliation: Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Vaquer-Alicea
authors.affiliation: Department of Pathology, Southwestern Medical Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO, USA.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.affiliation: Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., NL10.120, Dallas, TX, 75390, USA. marc.diamond@utsouthwestern.edu.
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008609:Mental Status Schedule; D018613:Microscopy, Confocal; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins
keywords: Alzheimer’s disease; Braak staging; Neuropathology; Propagation; Seeding; Tau