The Lesion Analysis of Cholinergic Neurons in 5XFAD Mouse Model in the Three-Dimensional Level of Whole Brain.
The Lesion Analysis of Cholinergic Neurons in 5XFAD Mouse Model in the Three-Dimensional Level of Whole Brain.
复制标题
全脑三维水平5XFAD小鼠模型胆碱能神经元损伤分析。
DOI：
10.1007/s12035-017-0621-4
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发表时间：
2017
影响因子：
5.1
通讯作者：
Youming Lu
中科院分区：
文献类型：
--
作者：
Huanhuan Yan;Pei Pang;Wenqi Chen;Houze Zhu;Henok K.A;Hao Li;Zuoze Wu;Xiao Ke;Jianhua Wu;Tongmei Zhang;Kai Pan;Lei Pei;Yunyun Han;Youming Lu
胆碱能系统对包括学习和记忆在内的许多高级大脑功能非常重要。胆碱能神经元，尤其是基底前脑中的胆碱能神经元，在一些神经退行性疾病中特别容易受到影响，如阿尔茨海默病(AD)。在此，我们研究了5个家族性AD突变对5XFAD小鼠胆碱能系统的影响。尽管在这个小鼠模型中已经研究了胆碱能系统，但AD小鼠的胆碱能缺陷从未在全脑三维(3D)重建中被系统地描绘出来。采用3D重建技术结合免疫组织化学(3D-IHC)和设计体视学方法，全面比较了不同年龄段5XFAD小鼠和C57BL/6对照小鼠胆碱能神经元和纤维的差异。在此，我们发现在5XFAD小鼠中，胆碱能纤维的损伤发生在胆碱能神经元丢失之前。阿尔茨海默病小鼠的胆碱能纤维损伤依次开始于杏仁核、皮质、海马体，然后是基底前脑。然而，基底前脑是5XFAD小鼠9月龄时第一个胆碱能神经元丢失的脑区，而C57BL/6对照组小鼠在15月龄时首次出现这种现象。此外，利用三维重建技术比较老年5XFAD小鼠和C57BL/6对照小鼠胆碱能系统的病变，可以直观地观察到病变的病变部位和严重程度。因此，3D-IHC提供了整个小鼠脑内胆碱能神经元的详细概述，这将有助于对小鼠大脑发育和病理的研究。
Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.