title: Proteopathic tau seeding predicts tauopathy in vivo.
abstract: Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Holmes
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Furman
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Tritia R
authors.initials: TR
authors.lastname: Yamasaki
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Hilda
authors.initials: H
authors.lastname: Mirbaha
authors.affiliation: Division of Oncology, Section of Stem Cell Biology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: William C
authors.initials: WC
authors.lastname: Eades
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Larisa
authors.initials: L
authors.lastname: Belaygorod
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, and marc.diamond@utsouthwestern.edu.
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015374:Biosensing Techniques; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D050505:Mutant Proteins; D016875:tau Proteins
keywords: aging; amyloid; dementia; neuropathology