GSK-3 is essential in the pathogenesis of Alzheimer's disease.
GSK-3 is essential in the pathogenesis of Alzheimer's disease.
复制标题
DOI：
10.3233/jad-2006-9s335
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
A. Takashima
中科院分区：
文献类型：
--
作者：
A. Takashima
糖原合成酶-3(GSK-3)是阿尔茨海默病(AD)发病过程中的关键分子。GSK-3β参与了成对螺旋丝(PHF)-tau的形成，tau是破坏神经元功能的神经纤维缠结(NFT)沉积的组成部分，也是AD神经变性的标志。GSK-3β与TPKI具有完全相同的寡核苷酸序列，TPKI最先从牛脑微管部分纯化而来。最初，我们发现GSK-3β参与了淀粉样β蛋白(Abeta)诱导的大鼠海马神经元死亡。在这篇综述中，我们讨论了我们的初步体外结果和更多的研究表明，Abeta通过损伤磷脂酰肌醇-3(PI3)/Akt信号激活GSK-3β；Abeta激活的GSK-3β诱导tau过度磷酸化、NFT形成、神经元死亡和突触丧失(所有这些都在AD脑中发现)；GSK-3β可以在体内诱导记忆障碍；并且抑制GSK-3α(GSK-3β的一个亚型)减少Abeta的产生。这些综合结果有力地表明，GSK-3的激活是大脑老化和AD中一系列有害事件的关键步骤，先于NFT和神经元死亡途径。因此，针对抑制GSK-3的治疗方法可能对这种毁灭性疾病的治疗是有益的。
Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3beta is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3beta has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3beta was involved in amyloid-beta (Abeta)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Abeta activates GSK-3beta through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Abeta-activated GSK-3beta induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3beta can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3beta) reduces Abeta production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.