Conformation Determines the Seeding Potencies of Native and Recombinant Tau Aggregates

作者：Benjamin Falcon, Annalisa Cavallini, Rachel C. Angers, Sarah J. Glover, Tracey K. Murray, Luanda Barnham, Samuel J. Jackson, Michael J. O'Neill, Adrian M. Isaacs, Michael L. Hutton, Philip G. Szekeres, Michel Goedert, Suchira Bose · 发表于：Journal of Biological Chemistry · 年份：2014 · DOI：10.1074/jbc.m114.589309 · 被引用次数：271 · 研究领域：Alzheimer's disease research and treatments、Prion Diseases and Protein Misfolding、Neurological diseases and metabolism

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 macro...