Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2024-10-25 DOI:10.1002/alz.14125

Sergio Escamilla, Raquel Badillos, Joan X. Comella, Montse Solé, Isabel Pérez‐Otaño, Jose V. Sánchez Mut, Javier Sáez‐Valero, Inmaculada Cuchillo‐Ibáñez

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引用次数: 0

Abstract

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.

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阿尔茨海默病患者大脑皮层中 NMDA 受体的突触和突触外分布

背景N-甲基-D-天冬氨酸受体（NMDARs）在阿尔茨海默病（AD）患者大脑中的突触内和突触外分布尚未得到研究，尽管它们对神经变性有贡献。我们对 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）进行了表征。结果发现 AD 组份中突触 GluN2B 和 GluN2A 的水平较低，而突触外 GluN2B 和 GluN1 的水平显著较高；GluN3A 的分布在 AD 中未受影响。我们还在突触外膜中发现了不同糖型的 GluN2B 和 GluN2A。讨论突触 NMDAR 亚基的减少，尤其是 GluN2B 的减少，可能是导致 AD 中突触传递失败的原因之一。此外，突触外 NMDAR 亚基的增加可能有利于激活 AD 中的兴奋毒性。阿尔茨海默病（AD）突触膜中的 GluN2B 和 GluN2A 含量较低。阿尔茨海默病突触外膜中的 GluN2B 和 GluN1 含量较高。突触外 GluN2B 和 GluN2A 的特定糖型。AD 突触 GluN2B 在 Tyr1472 处的磷酸化程度低。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.