Seizure-Induced Regulations of Amyloid-β, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity.
Seizure-Induced Regulations of Amyloid-β, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity.
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DOI：
10.1155/2016/2123748
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发表时间：
2016
影响因子：
3.1
通讯作者：
Chung HJ
中科院分区：
文献类型：
--
作者：
Jang SS;Royston SE;Lee G;Wang S;Chung HJ
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性认知能力下降。可溶性淀粉样蛋白-β (Aβ) 寡聚体的病理性积累会损害突触可塑性并导致癫痫发作，这两者都会导致 AD 中的认知功能障碍。然而，癫痫发作是否可以调节 Aβ 诱导的突触减弱仍不清楚。在这里，我们发现，单次电惊厥发作（ECS）后 2 天，大鼠海马中膜相关纹状体富含蛋白酪氨酸磷酸酶（STEP61）的蛋白表达增加，并降低其底物 N-甲基 D-天冬氨酸受体（NMDAR）亚基 GluN2B 和细胞外信号调节激酶 1/2（ERK1/2）的酪氨酸磷酸化。电子计算机系统。有趣的是，在单次 ECS 后 3-4 天，当 STEP61 水平恢复到基线时，观察到 ERK1/2 表达显着下降，APP 和 Aβ 水平增加。鉴于 Aβ 的病理水平增加了 STEP61 活性，STEP61 介导的 GluN2B 和 ERK1/2 去磷酸化导致 NMDAR 内化和 ERK1/2 失活，我们提出，STEP61 的上调和 GluN2B 和 ERK1/2 磷酸化的下调介导突触强度的代偿性减弱，以响应海马网络活动的急剧增强，而 ERK1/2 表达和 ERK1/2 的延迟下降APP 和 Aβ 表达的增加可能有助于维持这种突触减弱。
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Pathologic accumulation of soluble amyloid-β (Aβ) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD. However, whether seizures could regulate Aβ-induced synaptic weakening remains unclear. Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D-aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS. Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Aβ levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline. Given that pathologic levels of Aβ increase STEP61 activity and STEP61-mediated dephosphorylation of GluN2B and ERK1/2 leads to NMDAR internalization and ERK1/2 inactivation, we propose that upregulation of STEP61 and downregulation of GluN2B and ERK1/2 phosphorylation mediate compensatory weakening of synaptic strength in response to acute enhancement of hippocampal network activity, whereas delayed decrease in ERK1/2 expression and increase in APP and Aβ expression may contribute to the maintenance of this synaptic weakening.