Generation of Tau Aggregates and Clearance by Autophagy in an Inducible Cell Model of Tauopathy

We have studied the mechanism of aggregation in an inducible cell model of Tau pathology. When the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation Delta K280 is expressed, the cells develop aggregates, as seen by thioflavin S fluorescence, electron microscopy, and sarkosyl extraction methods. By contrast, mutants of Tau(RD) that are unable to generate beta-structure do not aggregate. Enhanced aggregation leads to enhanced toxicity, visible by live cell microscopy and LDH release assay. The aggregation process is initiated by the sequential cleavage of Tau(RD) which yields highly amyloidogenic fragments. This cleavage occurs only with proaggregant Tau(RD), and not with the nonaggregating mutants, indicating that beta-structure makes Tau(RD) vulnerable to both proteolytic degradation and aggregation. Aggregation is reversed by switching off the expression of Tau(RD), by inhibitor compounds, and by certain protease inhibitors. In all cases, the enhanced toxicity is rescued. The clearance of the aggregates involves autophagy, whereas proteasomal degradation plays only a minor role. Copyright (C) 2010 S. Karger AG, Basel