Pathological Reorganization of NMDA Receptors Subunits and Postsynaptic Protein PSD-95 Distribution in Alzheimer's Disease
Pathological Reorganization of NMDA Receptors Subunits and Postsynaptic Protein PSD-95 Distribution in Alzheimer's Disease
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DOI：
10.2174/15672050113106660170
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发表时间：
2014-01-01
影响因子：
2.1
通讯作者：
Savioz, Armand
中科院分区：
文献类型：
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作者：
Leuba, Genevieve;Vernay, Andre;Savioz, Armand
在阿尔茨海默病（AD）中，突触改变起着重要作用，并且通常与认知变化相关。为了更好地了解突触修饰，我们比较了AD和对照组大脑内嗅皮层（EC）和额叶皮层（FC; 9区）中NMDA受体和突触后蛋白PSD-95表达的变化。我们结合免疫组织化学和图像分析方法，定量连续切片上的PSD-95和NMDA受体GluN 1，GluN 2A和GluN 2B在EC和FC从25 AD和对照组的分布。使用多变量统计方法分析染色受体的密度以评估神经变性的影响。在这两个区域中，与对照组相比，AD中GluN 1受体亚基和PSD-95蛋白免疫染色的神经元轮廓的数量显著增加（3-6倍），而GluN 2A和GluN 2B受体亚基染色的神经元轮廓的数量相反地减少（3-4倍）。显著神经元分布的增加在对应于具有大锥体细胞的第3至5层的皮质带中更为突出。GluN 1或PSD-95染色阳性的神经元通常在连续切片的相同位置发现，并且它们也对抗tau抗体AD 2具有反应性，表明神经退行性过程。代表神经堆的免疫反应点的密度差异无统计学意义。总之，这些数据表明，GluN 1和PSD-95在神经元胞体中积累，但这不是GluN 2A和GluN 2B的情况，而神经细胞隔室较少受到修改。因此，NMDA受体亚基和PSD-95的分布模式的重要变化代表AD中的标志物，并且通过损害神经元网络，导致功能恶化。
In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.