title: Conformation determines the seeding potencies of native and recombinant Tau aggregates.
abstract: Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled "prion-like" species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent Tau remain unclear. Here, we have used a cell model to understand the relationships between Tau structure/phosphorylation and seeding by aggregated Tau species from the brains of mice transgenic for human mutant P301S Tau and full-length aggregated recombinant P301S Tau. Deletion of motifs (275)VQIINK(280) and (306)VQIVYK(311) abolished the seeding activity of recombinant full-length Tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic Tau aggregates that may account for the higher seeding activity of native assembled Tau. When added to aggregated Tau seeds from the brains of mice transgenic for P301S Tau, soluble recombinant Tau aggregated and acquired the molecular properties of aggregated Tau from transgenic mouse brain. We show that seeding is conferred by aggregated Tau that enters cells through macropinocytosis and seeds the assembly of endogenous Tau into filaments.
authors.affiliation: From the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Falcon
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cavallini
authors.affiliation: From the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom, Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Angers
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Glover
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Tracey K
authors.initials: TK
authors.lastname: Murray
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Luanda
authors.initials: L
authors.lastname: Barnham
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Samuel
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: the UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Szekeres
authors.affiliation: From the Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom, mg@mrc-lmb.cam.ac.uk.
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Eli Lilly and Co., Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom, and bose_suchira@lilly.com.
authors.forename: Suchira
authors.initials: S
authors.lastname: Bose
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011487:Protein Conformation; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D066329:Protein Aggregates; D016875:tau Proteins
keywords: Aggregation; Neurodegenerative Disease; Prion; Protein Conformation; Seed-competent Aggregation; Tau Protein; Tauopathy