BACKGROUNDSynaptic and extrasynaptic distribution of N‐methyl‐D‐aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite their contribution to neurodegeneration.METHODSWe have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well as post‐translational modifications, such as phosphorylation and glycosylation.RESULTSLower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions.DISCUSSIONReduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD.Highlights New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.

中文翻译：

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NMDA 受体在阿尔茨海默病患者皮层中的突触和突触外分布


背景尽管 N-甲基-D-天冬氨酸受体 （NMDAR） 对神经退行性变有贡献，但尚未解决阿尔茨海默病 （AD） 受试者大脑中 N-甲基-D-天冬氨酸受体 （NMDAR） 的突触和突触外分布问题。方法我们已经开发了一种方案，将突触膜和突触外膜与对照组和 AD 额叶皮层隔离开来。我们表征了 NMDAR 亚基 GluN2B 、 GluN2A 、 GluN1 和 GluN3A 的分布，以及翻译后修饰，如磷酸化和糖基化。结果在 AD 组分中发现突触 GluN2B 和 GluN2A 的高水平，而突触外 GluN2B 和 GluN1 水平显著升高;GluN3A 分布在 AD 中不受影响。我们还在突触外膜中鉴定了 GluN2B 和 GluN2A 的不同糖型。突触 Tyr1472 GluN2B 磷酸化在 AD 组分中显著降低。讨论突触 NMDAR 亚基的产生，特别是 GluN2B，可能导致 AD 中的突触传递失败。此外，突触外 NMDAR 亚基的增加可能有利于 AD 中兴奋性毒性的激活。亮点 从人类皮层分离突触和突触外膜的新方案。阿尔茨海默病 （AD） 突触膜中的 GluN2B 和 GluN2A 水平低。AD 突触外膜中的 GluN2B 和 GluN1 水平高。突触外 GluN2B 和 GluN2A 的特异性糖型。AD 中突触 GluN2B 中 Tyr1472 位点的磷酸化水平较低。