Centro de Biología Molecular Severo Ochoa, C/Nicolás Cabrera, 1. Universidad Autónoma de Madrid, Campus Cantoblanco. 28049 Madrid, Spain.
Neurobiol Dis. 2010 Mar;37(3):622-9. doi: 10.1016/j.nbd.2009.11.017. Epub 2009 Dec 11.
It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic mice that overexpress GSK3beta in forebrain regions including dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that GSK3 overexpression results in DG degeneration. To test whether tau protein modified by GSK3 plays a role in that neurodegeneration, we have brought GSK3 overexpressing mice to a tau knockout background. Our results indicate that the toxic effect of GSK3 overexpression is milder and slower in the absence of tau. Thus, we suggest that the hyperphosphorylated tau mediates, at least in part, the pathology observed in the brain of GSK3 overexpressing mice.
有人提出，神经元糖原合酶激酶 3（GSK3）活性的失调可能是阿尔茨海默病发病机制的一个关键特征。我们之前生成了过表达 GSK3β的转基因小鼠，其在前脑区域包括齿状回（DG）中过表达，DG 是参与学习和记忆获取的区域。我们发现 GSK3 的过表达导致 DG 退化。为了测试由 GSK3 修饰的 tau 蛋白是否在神经退行性变中起作用，我们将 GSK3 过表达的小鼠引入 tau 敲除背景。我们的结果表明，在没有 tau 的情况下，GSK3 过表达的毒性作用更温和、更缓慢。因此，我们认为过度磷酸化的 tau 至少部分介导了 GSK3 过表达小鼠大脑中观察到的病理。
