Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β
Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β
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DOI：
10.1111/j.1471-4159.2005.03363.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Kar, S
中科院分区：
文献类型：
--
作者：
Hawkes, C;Jhamandas, JH;Kar, S
糖原合成酶激酶-3 β（GSK-3 β）是一种多功能酶，参与多种生物学事件，包括发育、葡萄糖代谢和细胞死亡。其活性受Ser（9）残基磷酸化的抑制，受Tyr（216）磷酸化的上调。活化的GSK-3 β增加tau蛋白的磷酸化并诱导多种培养的神经元中的细胞死亡，而抑制GSK-3 β活性的磷脂酰肌醇-3（PI-3）激酶依赖性蛋白激酶B（Akt）的磷酸化是最佳表征的细胞存活信号传导途径之一。在本研究中，胆碱能免疫毒素192 IgG-皂草素被用来解决的潜在作用GSK-3 β基底前脑胆碱能神经元，这是优先脆弱的阿尔茨海默氏病（AD）的大脑退化。GSK-3 β与前脑胆碱能神经元的子集共定位，并且这些神经元的丧失伴随着基底前脑和海马中PI-3激酶、磷酸化-Ser（473）Akt和磷酸化-Ser（9）GSK-3 β水平的短暂降低以及磷酸化-tau水平的增加。在用192 IgG-皂草素处理的动物的这些脑区域中，总Akt、GSK-3 β、tau和磷酸-Tyr（216）GSK-3 β水平没有显著改变。GSK-3 β抑制剂LiCl的全身给药对对照大鼠的胆碱能标记物或磷酸化Ser（9）GSK-3 β水平没有显著影响，但排除了192-IgG皂草素诱导的PI-3激酶/磷酸化Akt、磷酸化Ser（9）GSK-3 β和磷酸化tau水平的改变，并且还部分保护胆碱能神经元免受免疫毒素的影响。这些结果提供了第一个证据，即GSK-3 β活性的增加，通过减少Ser（9）磷酸化，可以通过增强tau磷酸化至少部分介导192-IgG皂草素诱导的前脑胆碱能神经元的体内变性。在抑制GSK-3 β激酶活性后对这些神经元的部分保护表明GSK-3 β抑制剂在减轻AD中观察到的基底前脑胆碱能神经元损失方面可能具有治疗作用。
Glycogen synthase kinase-3 beta (GSK-3 beta) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser(9) residue and up-regulated by Tyr(216) phosphorylation. Activated GSK-3 beta increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3 beta activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3 beta in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3 beta co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser(473)Akt and phospho-Ser(9)GSK-3 beta levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3 beta, tau and phospho-Tyr(216)GSK-3 beta levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3 beta inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser(9)GSK-3 beta levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser(9)GSK-3 beta and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3 beta activity, via decreased Ser(9) phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3 beta kinase activity suggests a possible therapeutic role for GSK-3 beta inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.