Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
Provincial Key Laboratory of Cardiovascular and Cerebrovascular Drug Basic Research, Liaoning Medical University, Jinzhou 121001, Liaoning Province, China.
Neural Regen Res. 2013 Jul 25;8(21):1938-47. doi: 10.3969/j.issn.1673-5374.2013.21.002.
To stop the progression of Alzheimer's disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that al-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer's disease consisting of amyloid-beta peptide (1-42)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-beta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer's disease. Thus, al-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer's disease.
为了阻止阿尔茨海默病在早期的进展，有必要确定新的治疗靶点。我们检查了脑内富含纹状体的磷酸酶 61 在 12 个月龄 APPswe/PSEN1dE9 转基因小鼠脑组织中的表达。免疫组织化学显示，富含纹状体的磷酸酶 61 蛋白表达在 APPswe/PSEN1dE9 转基因小鼠的皮质和海马中显著增加，但磷酸化 N-甲基-D-天冬氨酸受体 2B 水平显著降低。体外由淀粉样β肽（1-42）处理的 C57BL/6 鼠皮质神经元组成的阿尔茨海默病细胞模型的 Western blot 显示，N-甲基-D-天冬氨酸受体拮抗剂缬草酸（AP5）显著抑制富含纹状体的磷酸酶 61 引起的活性增加。此外，在淀粉样β肽 1-42 处理的皮质神经元中，N-甲基-D-天冬氨酸受体 2B 的 Tyr1472 磷酸化受损，但富含纹状体的磷酸酶 61 的敲低增强了 N-甲基-D-天冬氨酸受体 2B 的磷酸化。总之，这些发现表明富含纹状体的磷酸酶 61 可以干扰 N-甲基-D-天冬氨酸受体的转运，并抑制阿尔茨海默病引起的学习和研究障碍的进展。因此，富含纹状体的磷酸酶 61 可能成为抑制阿尔茨海默病进展的新靶点。
