Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer's Disease.
Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer's Disease.
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DOI：
10.1016/j.neuroscience.2018.05.013
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发表时间：
2018-08-01
期刊：
影响因子：
3.3
通讯作者：
Singh AK
中科院分区：
文献类型：
--
作者：
Choi S;Won JS;Carroll SL;Annamalai B;Singh I;Singh AK
阿尔茨海默氏病（AD）是最常见的痴呆形式，通常伴有情绪和情感障碍以及癫痫发作。越来越多的证据表明，表达γ-氨基丁酸（GABA）的神经元在认知、情绪和癫痫易感性的调节中起重要作用，但目前对GABA能神经元病理在阿尔茨海默病（AD）中的作用还不清楚。在这里，我们报告，转基因小鼠表达人淀粉样蛋白前体蛋白瑞典-Deutch-爱荷华州突变体（APPSweDI）表现出早期损失的神经元表达GAD 67，GABA合成酶，提前海马CA 1区的锥体神经元的损失。APPSweDI小鼠GAD 67+神经元的丢失伴随着空间认知能力的下降以及焦虑样行为和红藻氨酸诱导的早期癫痫易感性的增加。在海马CA 1区，GAD 67+神经元表达高基础水平的神经元型一氧化氮合酶（nNOS）和亚硝化应激（硝基酪氨酸）。同样，原代皮质和海马神经元培养物中的GAD 67+神经元也表达高基础水平的nNOS，并因其高基础水平的亚硝化应激而响应较低的Aβ浓度而退化。鉴于GABA能神经元在认知和神经精神功能中的作用，本研究报告了nNOS介导的亚硝化应激在GABA能神经元功能障碍中的作用及其在AD认知和神经精神症状早期发展中的潜在参与。
Alzheimer’s disease (AD) is the most common form of dementia that is often accompanied by mood and emotional disturbances and seizures. There is growing body of evidence that neurons expressing γ-aminobutyric acid (GABA) play an important role in regulation of cognition, mood, and emotion as well as seizure susceptibility, but participation of GABAergic neuronal pathology in Alzheimer’s disease (AD) is not understood well at present. Here, we report that transgenic mice expressing human amyloid precursor protein Swedish-Deutch-Iowa mutant (APPSweDI) exhibit early loss of neurons expressing GAD67, a GABA synthesizing enzyme, in advance to the loss of pyramidal neurons in hippocampal CA1 region. The loss of GAD67+ neurons in APPSweDI mice accompanied with decreased spatial cognition as well as increased anxiety-like behaviors and kainic acid-induced seizure susceptibility at early phase. In the hippocampal CA1 region, GAD67+ neurons expressed high basal levels of neuronal nitric oxide synthase (nNOS) and nitrosative stress (nitrotyrosine). Similarly, GAD67+ neurons in primary cortical and hippocampal neuron cultures also expressed high basal levels of nNOS and degenerated in response to lower Aβ concentrations due to their high basal levels of nitrosative stress. Given the role of GABAergic neurons in cognitive and neuropsychiatric functions, this study reports the role of nNOS mediated nitrosative stress in dysfunction of GABAergic neurons and its potential participation in early development of cognitive and neuropsychiatric symptoms in AD.
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影响因子：
2.5
作者：
Gasulla, Javier;Calvo, Daniel J.
通讯作者：
Calvo, Daniel J.
DOI：
10.1073/pnas.94.22.12151
发表时间：
1997-10-28
影响因子：
11.1
作者：
Esclapez, M;Hirsch, JC;Bernard, C
通讯作者：
Bernard, C
影响因子：
3
作者：
Gholipour, Taha;Ghasemi, Mehdi;Dehpour, Ahmad Reza
通讯作者：
Dehpour, Ahmad Reza
影响因子：
4.8
作者：
Hayashi, Y;Nishio, M;Watanabe, Y
通讯作者：
Watanabe, Y
影响因子：
4.3
作者：
Chamberland S;Topolnik L
通讯作者：
Topolnik L