Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Neurochem. 2011 Nov;119(3):664-72. doi: 10.1111/j.1471-4159.2011.07450.x. Epub 2011 Sep 21.
Striatal-Enriched protein tyrosine Phosphatase of MW 61 kDa (STEP(61)) is a protein tyrosine phosphatase recently implicated in the pathophysiology of Alzheimer's disease (AD). STEP(61) is elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The elevated levels of active STEP(61) down-regulate surface expression of GluN1/GluN2B (formerly NR1/NR2B) receptor complexes, while genetically reducing STEP levels rescues both the biochemical and cognitive deficits in a triple transgenic AD mouse model (3xTg-AD). Here, we show that increased STEP(61) also plays a role in beta amyloid (Aβ)-mediated internalization of the α-amino-3-hydroxy-5-methyl-4-(AMPA) receptor (AMPAR) subunits GluA1/GluA2 (formerly GluR1/GluR2). We purified Aβ oligomers and determined that oligomers, but not monomers, lead to endocytosis of GluA1/GluA2 receptors in cortical cultures. The decrease in GluA1/GluA2 receptors is reversed in the progeny of STEP knock-out (KO) mice crossed with Tg2576 mice, despite elevated levels of Aβ. These results provide strong support for the hypothesis that STEP(61) is required for Aβ-mediated internalization of GluA1/GluA2 receptors.
MW61kDa 富含纹状体的蛋白酪氨酸磷酸酶（STEP（61））是一种蛋白酪氨酸磷酸酶，最近被认为与阿尔茨海默病（AD）的病理生理学有关。STEP（61）在人类 AD 前额叶皮层和几种 AD 小鼠模型的皮层中升高。活性 STEP（61）的升高水平下调 GluN1/GluN2B（以前称为 NR1/NR2B）受体复合物的表面表达，而遗传降低 STEP 水平可挽救三重转基因 AD 小鼠模型（3xTg-AD）中的生化和认知缺陷。在这里，我们表明增加的 STEP（61）也在β淀粉样蛋白（Aβ）介导的 AMPA 受体（AMPAR）亚基 GluA1/GluA2（以前称为 GluR1/GluR2）的内化中起作用。我们纯化了 Aβ寡聚体，并确定寡聚体而不是单体导致皮质培养物中 GluA1/GluA2 受体的内吞作用。尽管 Aβ水平升高，但与 Tg2576 小鼠杂交的 STEP 敲除（KO）小鼠的后代中 GluA1/GluA2 受体的减少得到逆转。这些结果为 STEP（61）是 Aβ 介导的 GluA1/GluA2 受体内化所必需的假设提供了强有力的支持。
