Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration
Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration
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DOI：
10.1016/j.neurobiolaging.2005.06.010
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发表时间：
2006-09-01
影响因子：
4.2
通讯作者：
Hernandez, Felix
中科院分区：
文献类型：
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作者：
Engel, Tobias;Lucas, Jose J.;Hernandez, Felix
在这里，我们已经测试了tau蛋白修饰无论是通过点突变或过度磷酸化，可以发挥最大的致病作用，或者如果相反，两种类型的tau蛋白修饰可以协同作用，以诱导神经病理学。为此，我们将过表达酶GSK-3 β的转基因小鼠（泰特/GSK-3 β小鼠）与表达具有三重FTDP-17突变的Tau的转基因小鼠（VLW小鼠）组合，所述Tau形成前纤维状tau聚集体。泰特/GSK-3 β/VLW转基因小鼠在海马神经元中显示tau过度磷酸化。这伴随着硫磺素-S染色，以及在宽度上类似于在tauophaties中发现的那些的细丝的形成。最后，在泰特/GSK-3 β小鼠中观察到的海马齿状回萎缩在TeUGSK-3 β/VLW小鼠中发展得更快。所有这些形态学和生物化学数据表明，两种类型的tau修饰具有协同作用，并且GSK-3抑制剂用于AD治疗的潜力也扩展到由tau基因中的点突变引起的tau蛋白病。(c)2005年由Elsevier Inc.出版
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.