Early involvement of small inhibitory cortical interneurons in Alzheimer's disease
Early involvement of small inhibitory cortical interneurons in Alzheimer's disease
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DOI：
10.1007/s00401-006-0068-6
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发表时间：
2006-08-01
影响因子：
12.7
通讯作者：
Schneider, Julie A.
中科院分区：
文献类型：
--
作者：
Koliatsos, Vassilis E.;Kecojevic, Aleksandar;Schneider, Julie A.
对皮质损伤的急性模型的研究已经揭示了一群小的GABA能中间神经元，其被诱导以增加其神经元型一氧化氮（NO）合酶（nNOS）的低组成性表达。在某些情况下，这种激活可能在NO介导的锥体神经元变性中起作用。在这份报告中，我们探讨了不同类别的皮质nNOS（+）（氮能）神经元的解剖，重点是小的中间神经元，在内侧颞叶的受试者与阿尔茨海默病（AD）从两个特征良好的队列，巴尔的摩纵向研究老化（BLSA）和宗教秩序研究（ROS）。我们发现，小calbindin（+）皮质中间神经元诱导高水平的NADPHd/nNOS反应性在AD的早期和丰富的领域与新兴的神经病理学，即，在内嗅皮层的Braak边缘阶段的开始，在海马CA 1在成熟的边缘阶段和颞叶新皮层在边缘阶段的晚期。这种模式在研究的两个AD队列中的年轻队列（BLSA）中是稳健和显著的，但在老年队列（ROS）中仍是一种趋势。在最佳制备的材料中，我们发现这些中间神经元的数量与神经元细胞死亡的标志物（例如，半胱天冬酶-3活化）之间存在显著相关性。我们的研究结果表明，小的皮质抑制性中间神经元代表一个广泛的信号系统，诱导更高水平的NADPHd/nNOS的表达早期在边缘-边缘-新皮质序列的AD进展。我们建议，nNOS/NO信号在这些中间神经元启动可以作为早期皮质损伤的AD的标志。抑制性中间神经元和NO在与AD相关的特定神经病理学的阐述中所发挥的特定作用，即A β和神经元沉积物和细胞死亡，值得在实验动物模型中进一步探索。
Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, A beta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.