Conformation Determines the Seeding Potencies of Native and Recombinant Tau Aggregates

• Published in: The Journal of biological chemistry Vol. 290; no. 2; pp. 1049 - 1065
• Main Authors: Falcon, Benjamin, Cavallini, Annalisa, Angers, Rachel, Glover, Sarah, Murray, Tracey K., Barnham, Luanda, Jackson, Samuel, O'Neill, Michael J., Isaacs, Adrian M., Hutton, Michael L., Szekeres, Philip G., Goedert, Michel, Bose, Suchira
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Aggregation; Animals; Brain - metabolism; Brain - pathology; Cytoskeleton - metabolism; Cytoskeleton - pathology; Disease Models, Animal; HEK293 Cells; Humans; Mice; Mice, Transgenic; Neurobiology; Neurodegenerative Disease; Phosphorylation; Prion; Protein Aggregates; Protein Aggregation, Pathological - metabolism; Protein Conformation; Seed-competent Aggregation; Tau Protein; tau Proteins - biosynthesis; tau Proteins - chemistry; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - pathology; Tauopathy; Aggregation; Neurodegenerative Disease; Tau Protein; Seed-competent Aggregation; Protein Conformation; Prion; Tauopathy
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.589309

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 275VQIINK280 and 306VQIVYK311 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. Characteristics of seed-competent Tau are unknown. Native Tau aggregates have a higher seeding potency than recombinant Tau aggregates. Recombinant Tau acquires the conformation and potency of native Tau aggregates by seeded assembly. Conformation determines the seeding potencies of Tau aggregates. Understanding the properties of seed-competent Tau gives insight into disease mechanisms.