Avila Jesús, Hernández Félix
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Expert Rev Neurother. 2007 Nov;7(11):1527-33. doi: 10.1586/14737175.7.11.1527.
Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer's disease, the extracellular senile plaques made of beta-amyloid and the intracellular neurofibrillary tangles made of hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of beta-amyloid as well as to respond to this peptide. The use of several transgenic models overexpressing GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and has been demonstrated to prevent tau phosphorylation. In this review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer's disease therapy, as well as some of their potential problems.
糖原合酶激酶（GSK）-3被认为是阿尔茨海默病两个组织病理学特征之间的联系纽带，这两个特征分别是由β-淀粉样蛋白构成的细胞外老年斑和由过度磷酸化的tau蛋白构成的细胞内神经原纤维缠结。因此，GSK-3是主要的tau激酶之一，它可修饰神经原纤维缠结中tau蛋白的多个位点。此外，GSK-3能够调节β-淀粉样蛋白的生成并对该肽作出反应。使用多种过表达GSK-3的转基因模型与神经元死亡、tau过度磷酸化以及认知能力下降有关。锂是一种广泛用于治疗情感障碍的药物，在治疗相关浓度下可抑制GSK-3，并且已被证明可预防tau磷酸化。在本综述中，我们总结了所有这些数据，并讨论了GSK-3抑制剂用于阿尔茨海默病治疗的潜力以及它们的一些潜在问题。
