Time course of Tau toxicity and pharmacological prevention in a cell model

Publication date: Available online 3 May 2017
Source:Neurobiology of Aging
Author(s): Marcus Pickhardt, Jacek Biernat, Sabrina Hübschmann, Frank Dennissen, Thomas Timm, Annukka Aho, Eva-Maria Mandelkow, Eckhard Mandelkow
The aggregation of Tau protein is a hallmark of neurodegenerative diseases including Alzheimer Disease. Previously we generated a cell model of Tauopathy based on the 4-repeat domain with the FTDP-17 mutation ΔK280 (Tau^4RDΔK) which is expressed in a regulatable fashion (tet-on). The deletion variant ΔK280 is highly amyloidogenic and forms fibrous aggregates in neuroblastoma N2a cells staining with the reporter dye Thioflavin-S. The aggregation of Tau^4RDΔK is toxic, contrary to wildtype or anti-aggregant variants of the protein.Using a novel approach for monitoring Tau aggregation and toxicity in situ by combination of microscopic analysis with FACS and biochemical analysis of cells enabled the dissection of the aggregating species which cause a time dependent increase of toxicity. The dominant initiating step is the dimerization of Tau^4RDΔK which leads to further aggregation, induces a strong increase in reactive oxygen species (ROS) and cytoplasmic Ca²⁺ which damage the membranes and cause cell death. Tau-based treatments using Tau aggregation inhibitors reduce both soluble oligomeric and fully aggregated Tau species and decrease their toxicity.



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