GSK-3α regulates production of Alzheimer's disease amyloid-β peptides
GSK-3α regulates production of Alzheimer's disease amyloid-β peptides
复制标题
DOI：
10.1038/nature01640
复制
发表时间：
2003-05-22
期刊：
影响因子：
64.8
通讯作者：
Klein, PS
中科院分区：
文献类型：
--
作者：
Phiel, CJ;Wilson, CA;Klein, PS
阿尔茨海默病与淀粉样β蛋白(Abeta)多肽的产生和聚集增加有关(1)。Aβ多肽是由淀粉样前体蛋白(APP)通过顺序蛋白分解，由天冬氨酸蛋白酶BACE(2)催化，然后依赖于早老素的伽马分泌酶裂解(3)而得到的。早老素与尼古丁(4，5)、APH-1和PEN-2相互作用(参考文献)。6)，所有这些都是伽玛分泌酶功能所必需的。早老素还与α-连环蛋白、β-连环蛋白(7，8)和糖原合成酶-3β(GSK-3β)(9-11)相互作用，但这些蛋白在伽玛分泌酶活性中的功能作用尚未确定。在这里，我们展示了治疗浓度的锂，一种GSK-3抑制剂(12)，通过干扰伽玛分泌酶步骤中APP的裂解来阻止Aβ多肽的产生，但不抑制Notch加工。重要的是，锂还可以阻止过度产生APP的小鼠大脑中Abeta多肽的积累。在此设置中锂的目标是GSK-3pha，这是APP最大处理所需的。由于GSK-3还使神经原纤维缠结的主要成分tau蛋白磷酸化，抑制GSK-3α提供了一种新的方法来减少淀粉样斑块和神经原纤维缠结的形成，这是阿尔茨海默病的两个病理特征。
Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides(1). Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE(2), followed by presenilin-dependent gamma-secretase cleavage(3). Presenilin interacts with nicastrin(4,5), APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin(7,8) and glycogen synthase kinase-3beta (GSK-3beta)(9-11), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor(12), block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.