Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo.
Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo.
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DOI：
10.1523/jneurosci.0607-11.2011
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发表时间：
2011-08-03
期刊：
影响因子：
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通讯作者：
Cirrito JR
中科院分区：
文献类型：
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作者：
Verges DK;Restivo JL;Goebel WD;Holtzman DM;Cirrito JR
大脑细胞外空间内淀粉样蛋白-β (Aβ) 的浓度是肽是否会聚集成对阿尔茨海默病 (AD) 发病机制很重要的有毒物质的决定因素之一。某些类型的突触活动可以调节 Aβ 水平。在这里，我们展示了两种不同的机制，它们同时被 NMDA 受体激活，并在活体小鼠中以相反的方向调节脑间质液 (ISF) Aβ 水平。 ISF Aβ 水平会升高或降低，具体取决于大脑局部施用的 NMDA 剂量。低剂量的 NMDA 会增加动作电位和突触传递，从而导致突触 Aβ 生成增加。相比之下，高剂量的 NMDA 会激活导致 ERK（细胞外调节激酶）激活的信号通路，从而减少 APP 转化为 Aβ 的过程。尽管突触活动显着升高，但 APP 处理导致的 Aβ 抑制仍然发生。这两种突触机制同时活跃，它们之间的平衡决定了 ISF Aβ 水平是升高还是降低。 NMDA 受体拮抗剂会增加 ISF Aβ 水平，表明这些受体的基础活性通常会抑制体内 Aβ 水平。这对于理解正常的 Aβ 代谢以及 AD 发病机制具有重要意义。
The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer’s disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis.