Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration

被引:88
作者
Engel, Tobias
Lucas, Jose J.
Gomez-Ramos, Pilar
Moran, Maria A.
Avila, Jesus
Hernandez, Felix [1 ]
机构
[1] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, CSIC, UAM,Fac Ciencias, E-28049 Madrid, Spain
[2] Univ Autonoma Madrid, Fac Med, Dept Morfol, E-28029 Madrid, Spain
关键词
Alzheimer's disease; FTDP-17; GSK-3; transgenic mice; tau; paired helical filaments;
D O I
10.1016/j.neurobiolaging.2005.06.010
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Here we have tested whether tau modification either by point mutation or by hyperphosphorylation can exert maximal pathogenic effects or if, on the contrary, both types of tau modifications can act synergistically to induce neuropathology. For this, we have combined transgenic mice overexpressing the enzyme GSK-3 beta (Tet/GSK-3 beta mice), with transgenic mice expressing Tau with a triple FTDP-17 mutation which develop prefibrillar tau-aggregates (VLW mice). Tet/GSK-3 beta/VLW transgenic mice show tau hyperphosphorylation in hippocampal neurons. This is accompanied by thioflavin-S staining, and formation of filaments similar in width to those found in tauophaties. Finally, the atrophy of the hippocampal dentate gyrus observed in Tet/GSK-3 beta mice develops much faster in TeUGSK-3 beta/VLW mice. All these morphological and biochemical data demonstrate that there is a synergistic contribution of both types of tau modifications and that the potential of GSK-3 inhibitors for AD therapeutics also extends to tauopathies caused by point mutations in tau gene. (c) 2005 Published by Elsevier Inc.
引用
收藏
页码:1258 / 1268
页数:11
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