Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61.
Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61.
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DOI：
10.1523/jneurosci.0157-10.2010
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发表时间：
2010-04-28
期刊：
影响因子：
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通讯作者：
Lombroso PJ
中科院分区：
文献类型：
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作者：
Kurup P;Zhang Y;Xu J;Venkitaramani DV;Haroutunian V;Greengard P;Nairn AC;Lombroso PJ
淀粉样β蛋白(Aβ)参与阿尔茨海默病(AD)的发病机制，并可能通过增加离子型谷氨酸受体的内化而导致认知障碍。纹状体富含蛋白酪氨酸磷酸酶61(STEP61)部分针对突触后终末，参与了这一过程。在这里，我们显示STEP61水平在第一年在Tg2576小鼠的大脑皮质中逐渐增加，以及在人类AD大脑的前额叶皮质中。STEP61的增加与更大的阶跃活性、NR2B亚基的磷酸化酪氨酸1472的去磷酸化以及神经细胞膜上NR1和NR2B亚基的减少有关。生物素化实验表明，富集液处理也增加了小鼠皮质培养物中STEP61的水平，降低了NR1/NR2B的丰度。在步骤敲除培养中，Aβ处理未能诱导NMDAR内化。STEP61水平升高的机制可能与泛素蛋白酶体系统(UPS)有关。阻断蛋白酶体导致STEP61水平升高。此外，在Aβ处理的野生型大脑皮层切片和12个月的Tg2576大脑皮层中，STEP61-泛素结合物增加。这些发现揭示了一种新的机制，即β介导的STEP61的积聚导致NR1NR2B受体内化增加，这可能是AD认知障碍的原因之一。
Amyloid beta (Aβ) is involved in the etiology of Alzheimer's disease (AD) and may contribute to cognitive deficits by increasing internalization of ionotropic glutamate receptors. STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61), which is targeted in part to the postsynaptic terminal, has been implicated in this process. Here we show that STEP61 levels are progressively increased in the cortex of Tg2576 mice over the first year, as well as in prefrontal cortex of human AD brains. The increased STEP61 was associated with greater STEP activity, dephosphorylation of phospho-tyr1472 of the NR2B subunit, and decreased NR1 and NR2B subunits on neuronal membranes. Treatment with -enriched medium also increased STEP61 levels and decreased NR1/NR2B abundance in mouse cortical cultures as determined by biotinylation experiments. In STEP knock-out cultures, Aβ treatment failed to induce NMDAR internalization. The mechanism for the increase in STEP61 levels appears to involve the ubiquitin proteasome system (UPS). Blocking the proteasome resulted in elevated levels of STEP61. Moreover, STEP61-ubiquitin conjugates were increased in wild-type cortical slices upon Aβ treatment as well as in 12-month Tg2576 cortex. These findings reveal a novel mechanism by which Aβ-mediated accumulation of STEP61 results in increased internalization of NR1/NR2B receptor that may contribute to the cognitive deficits in AD.