Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
Channels (Austin). 2010 Sep-Oct;4(5):347-50. doi: 10.1523/JNEUROSCI.0157-10.2010. Epub 2010 Sep 6.
Amyloid beta (Aβ), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Aβ downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP₆₁). More recent findings confirm that STEP₆₁ plays an important role in Aβ-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP₆₁ levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP₆₁ is due to disruption in the normal degradation of STEP₆₁ by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP₆₁ contributes to aspects of the pathophysiology in Alzheimer's disease. Exogenous application of Aβ-enriched conditioned medium (7PA2-CM) to wild-type cortical cultures results in a loss of GluN1/GluN2B subunits from neuronal membranes. Abeta-mediated NMDAR internalization does not occur in STEP knock-out cultures, but is rescued by the addition of active TAT-STEP to the cultures prior to Aβ treatment.
淀粉样蛋白β（Aβ）被认为是阿尔茨海默病的致病因素，已知其会影响谷氨酸受体的转运。先前的研究表明，Aβ 通过激活纹状体丰富的蛋白酪氨酸磷酸酶 61（STEP₆₁）下调 N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）的表面表达。最近的研究结果证实，STEP₆₁ 在 Aβ 诱导的 NMDAR 内吞作用中发挥重要作用。人 AD 前额叶皮层和几种 AD 小鼠模型的皮层中 STEP₆₁ 水平升高。STEP₆₁ 水平和活性的增加导致 GluN1/GluN2B 受体复合物从神经元表面膜中去除。STEP₆₁ 的升高是由于泛素蛋白酶体系统对 STEP₆₁ 的正常降解受到破坏。在这里，我们简要讨论了其他研究，以支持我们的假说，即 STEP₆₁ 有助于阿尔茨海默病的病理生理学的各个方面。将富含 Aβ 的条件培养基（7PA2-CM）外源性应用于野生型皮质培养物会导致神经元膜上的 GluN1/GluN2B 亚基丢失。在 STEP 敲除培养物中不会发生 Abeta 介导的 NMDAR 内化，但在 Aβ 处理前向培养物中添加活性 TAT-STEP 可挽救。
