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首页> 外文期刊>Nature reviews. Urology >Kidney cancer: Sunitinib has similar efficacy irrespective of age in mRCC.
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Kidney cancer: Sunitinib has similar efficacy irrespective of age in mRCC.

机译：肾癌：舒尼替尼的疗效与mRCC的年龄无关。

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It is becoming increasingly clear that aberrant neuronal activity can be the cause and the result of amyloid beta production. Synaptic activation facilitates non-amyloidogenic processing of amyloid precursor protein (APP) and cell survival, primarily through synaptic NMDA receptors (NMDARs) and perhaps specifically those containing GluN2A-subunits. In contrast, extrasynaptic and GluN2B-containing NMDARs promote beta-secretase cleavage of APP into amyloid-beta (Aβ). The opposing nature of these NMDAR populations is reflected in their control over cell survival and death pathways. Subtle changes in glutamate homeostasis may shift the balance between these pathways and could play a role in Alzheimer's disease (AD). Indeed, Aβ production, regional loss of brain connectivity and neurodegeneration correlate with neuronal activity in AD patients. From another perspective, Aβ oligomers (Aβo) alter neuronal signaling through several mechanisms involving NMDARs and intracellular calcium mishandling. While Aβo affect multiple receptors, GluN2B-NMDARs have emerged as primary mediators of altered synaptic plasticity and neurotoxicity. Memantine and its successor, NitroMemantine, are efficient at blocking or reversing the deleterious actions of Aβo largely due to their selectivity for extrasynaptic NMDARs. Recently, Aβo were shown to trigger astrocytic release of glutamate to the extrasynaptic space where it activates NMDARs to promote further Aβ production and synaptic depression. Combined with the reciprocal regulation between neuronal activity and Aβ production, extrasynaptic glutamate release adds to a maladaptive model and ultimately results in synaptotoxicity and neurodegeneration of AD. Extrasynaptic NMDAR antagonists remain as a promising therapeutic avenue by interfering with this cascade.
机译：越来越清楚的是，异常的神经元活动可能是淀粉样β产生的原因和结果。突触激活主要通过突触NMDA受体（NMDARs），特别是那些含有GluN2A亚基的受体，促进非淀粉样蛋白淀粉样前体蛋白（APP）的加工和细胞存活。相反，突触外和含GluN2B的NMDAR促进APP的β-分泌酶切割成淀粉样β（Aβ）。这些NMDAR种群的相反性质反映在它们对细胞存活和死亡途径的控制中。谷氨酸稳态的细微变化可能会改变这些途径之间的平衡，并可能在阿尔茨海默氏病（AD）中发挥作用。实际上，AD患者中Aβ的产生，大脑连接性的局部丧失和神经变性与神经元活动相关。从另一个角度看，Aβ低聚物（Aβo）通过涉及NMDAR和细胞内钙错误处理的几种机制改变神经元信号传导。虽然Aβo影响多种受体，但GluN2B-NMDARs已成为改变突触可塑性和神经毒性的主要介质。美金刚及其后继者NitroMemantine在阻止或逆转Aβo的有害作用方面非常有效，这主要是由于它们对突触外NMDAR的选择性。最近，显示Aβo触发谷氨酸向突触外空间的星状释放，并在其中激活NMDARs来促进进一步的Aβ产生和突触抑制。结合神经元活性和Aβ产生之间的相互调节，突触外谷氨酸的释放增加了适应不良的模型，最终导致AD的突触毒性和神经变性。突触外NMDAR拮抗剂通过干扰这种级联反应仍然是有希望的治疗途径。

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