Extracellular Monomeric Tau Protein Is Sufficient to Initiate the Spread of Tau Protein Pathology

• Published in: The Journal of biological chemistry 2014-01, Vol.289 (2), p.956-967
• Main Authors: Michel, Claire H., Kumar, Satish, Pinotsi, Dorothea, Tunnacliffe, Alan, St. George-Hyslop, Peter, Mandelkow, Eckhard, Mandelkow, Eva-Maria, Kaminski, Clemens F., Kaminski Schierle, Gabriele S.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease; Amyloid; Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Endocytosis; Endosomes - metabolism; Exocytosis; Extracellular Space - metabolism; Fluorescence Lifetime Imaging Microscopy; Humans; Lysosomes - metabolism; Microscopy, Confocal; Microscopy, Electron; Models, Biological; Neurobiology; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - ultrastructure; Neurons - metabolism; Neurons - pathology; Propagation; Protein Aggregation; Superresolution Microscopy; Tau; tau Proteins - metabolism; Tauopathies - metabolism; Transport Vesicles - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.515445

Understanding the formation and propagation of aggregates of the Alzheimer disease-associated Tau protein in vivo is vital for the development of therapeutics for this devastating disorder. Using our recently developed live-cell aggregation sensor in neuron-like cells, we demonstrate that different variants of exogenous monomeric Tau, namely full-length Tau (hTau40) and the Tau-derived construct K18 comprising the repeat domain, initially accumulate in endosomal compartments, where they form fibrillar seeds that subsequently induce the aggregation of endogenous Tau. Using superresolution imaging, we confirm that fibrils consisting of endogenous and exogenous Tau are released from cells and demonstrate their potential to spread Tau pathology. Our data indicate a greater pathological risk and potential toxicity than hitherto suspected for extracellular soluble Tau. The aggregation and stereotypic spreading of Tau protein is associated with Alzheimer disease. Monomeric Tau enters neurons and nucleates and engages endogenous Tau to aggregate. Endocytosis of soluble Tau triggers aggregation in vesicles and is sufficient to initiate the spreading of pathological species. Increased levels of extracellular monomeric Tau may increase the risk of developing tauopathies.