%0 Thesis
%A Kaniyappan, Senthilvelrajan
%T Structural and Functional Characterization of Neurotoxic Oligomers of Pro-aggregant Tau Repeat Domain
%I Rheinische Friedrich-Wilhelms-Universität Bonn
%V Dissertation
%M DZNE-2024-00798
%P 127 pages, 41 figures
%D 2016
%Z Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, 2015
%X Tau protein is a microtubule associated protein present abundantly in the neurons of the central nervous system where it stabilizes the axonal microtubules thereby providing structural architecture for the axons of neurons. Aggregation of Tau occurs in many neurodegenerative diseases collectively termed tauopathies including Alzheimer disease (AD) and frontotemporal dementia (FTD). The mutation ΔK280 of Tau was originally discovered in cases of FTD (Rizzu et al., 1999). In vitro it leads to a pronounced propensity of the protein to aggregate (Barghorn et al., 2000). The repeat domain of Tau protein with this pro-aggregant mutation (TauRDΔ) induces toxicity in transgenic mice and organotypic hippocampal slice culture models (Sydow et al., 2011, Messing et al., 2013). One current concept of Tau-mediated toxicity in Alzheimer disease and related tau dependent pathologies is that it is based on low-n oligomeric species, rather than higher aggregated forms (fibers and neurofibrillary tangles). To test this we characterized oligomers from TauRDΔ protein assembled and purified in vitro. Since Tau oligomers are in dynamic equilibrium during aggregation, we tried to capture and stabilize only the oligomeric forms of Tau using EGCG (Epigallocatechin gallate). EGCG reduces the formation of fibrils and increases the SDS stable oligomers. However, the oligomers are not separable by gel filtration chromatography. Therefore we stabilized the tau oligomers using a low concentration of glutaraldehyde as a cross-linking reagent. This yielded SDS stable low-n oligomers predominantly in the form of dimers, trimers, tetramers with very low amounts of higher order species. The cross-linked TauRDΔ oligomers can be purified by hydrophobic interaction chromatography with  95
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%U https://pub.dzne.de/record/270420