中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (3): 447-453.doi: 10.4103/1673-5374.179057

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

视网膜大量表达β位淀粉样前体蛋白裂解酶1是阿尔茨海默病早期诊断的生物标志物？

  

  • 收稿日期:2015-12-22 出版日期:2016-03-15 发布日期:2016-03-15
  • 基金资助:

    国家自然科学基金（81371011, 81400399, 81471107）；中南大学创新技术项目（2015CXS022）；中南大学基础研究基金（2010QZZD022）；国家重点技术研究与发展项目（2012BAK14B03）；中南大学研究生论文创新基金（2011ssxt106）

BACE1 in the retina: a sensitive biomarker for monitoring early pathological changes in Alzheimer’s disease

Lan Li 1, Jia Luo 1, Dan Chen 1, Jian-bin Tong 2, Le-ping Zeng 1, Yan-qun Cao 1, Jian Xiang 1, Xue-gang Luo 1, Jing-ming Shi 3, Hui Wang 1,Ju-fang Huang 1   

  1. 1 Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
    2 Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
    3 Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • Received:2015-12-22 Online:2016-03-15 Published:2016-03-15
  • Contact: Hui Wang, Ph.D. or Ju-fang Huang, Ph.D., wanghuixsh@163.com or huangjufang@mail.csu.edu.cn.
  • Supported by:

    This work was supported by the National Natural Science Foundation of China (to JFH, DC, JBT), No. 81371011, 81400399, 81471107; a grant from the Project of Innovation-driven Plan of Central South University (to DC), No. 2015CXS022; a grant from the National Key Technologies Research and Development Program of China (to JFH), No. 2012BAK14B03; Fundamental Research Funds of Central South University of China (to HW), No. 2010QZZD022; Graduate Thesis Innovation Foundation of Central South University of China (to LL), No. 2011ssxt106.

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摘要：

由于缺少有效的早期观察指标，阿尔茨海默病一旦确诊便已经进入临床发病期，因此寻找早期的诊断指标具有重要意义。以往研究显示，阿尔茨海默病不仅会导致患者脑组织发生病变，也常累及视网膜。实验以易于观察和干扰处理的视网膜为窗口，以β位淀粉样前体蛋白裂解酶1（BACE-1）为切入点，研究其在视网膜和脑中表达的时距差异，以期为该疾病早期监测找到合适的生物标志物。实验以3，6，8月龄的APP/PS-1转基因小鼠作为实验组，等月龄C57/BL6野生小鼠作为对照组。（1）Morris水迷宫检测结果显示，各月龄野生组小鼠的逃避潜伏期和穿越平台区域次数无明显差异。APP/PS-1转基因小鼠在3月龄时学习记忆能力无明显改变；6月龄时，在水迷宫学习的第3天和第4天的逃避潜伏期延长，而且在记忆测试中穿过平台区域次数明显减少，8月龄时学习记忆能力进一步变差。（2）免疫组织化学技术方法检测的BACE-1表达:在脑内，各月龄野生组及3月龄转基因组未见BACE-1斑块出现，但6月龄和8月龄的转基因组小鼠嗅皮质区、海马区和额项皮质区均出现 BACE-1斑块。在视网膜，3月龄野生组小鼠视网膜未见明显BACE-1阳性产物表达，6月龄及8月龄野生组小鼠视网膜节细胞层、内网层以及外网层略有表达。与同月龄的野生组小鼠相比，3月龄转基因组小鼠视网膜节细胞层的BACE-1表达明显增加，6月龄和8月龄时视网膜节细胞层、内网层、外网层BACE-1表达有显著增强。这些结果提示BACE-1在转基因组小鼠视网膜的表达变化，在时间上明显早于脑内BACE-1异常改变出现的时间以及动物行为异常出现的时间。视网膜BACE-1的改变是AD早期病理改变，针对其的诊断方法将很可能有利于早期AD的诊断。

关键词: 神经再生, 神经退行性变, 阿尔茨海默病, 视网膜, β位淀粉样前体蛋白裂解酶1, APP/PS1双转基因小鼠

Abstract:

Because of a lack of sensitive biomarkers, the diagnosis of Alzheimer’s disease (AD) cannot be made prior to symptom manifestation. Therefore, it is crucial to identify novel biomarkers for the presymptomatic diagnosis of AD. While brain lesions are a major feature of AD, retinal pathological changes also occur in patients. In this study, we investigated the temporal changes in β-site APP-cleaving enzyme 1 (BACE1) expression in the retina and brain to determine whether it could serve as a suitable biomarker for early monitoring of AD. APP/PS-1 transgenic mice, 3, 6 and 8 months of age, were used as an experimental group, and age-matched C57/BL6 wild-type mice served as the control group. In the Morris water maze test, there were no significant differences in escape latency or in the number of crossings in the target area among mice of different ages. Compared with wild-type mice, no changes in learning or memory abilities were detected in transgenic mice at 3 months of age. However, compared with wild-type mice, the escape latency was significantly increased in transgenic mice at 6 months, starting on day 3, and at 8 months, starting on day 2, during Morris water maze training. In addition, the number of crossings of the target area was significantly decreased in transgenic mice. The learning and memory abilities of transgenic mice were further worsened at 8 months of age. Immunohistochemical staining revealed no BACE1 plaques in wild-type mice at 3, 6 or 8 months or in transgenic mice at 3 months, but they were clearly found in the entorhinal cortex, hippocampus and prefrontal cortex of transgenic mice at 6 and 8 months. BACE1 expression was not detected in the retina of wild-type mice at 3 months, but weak BACE1 expression was detected in the ganglion cell layer, inner plexiform layer and outer plexiform layer at 6 and 8 months. In transgenic mice, BACE1 expression in the ganglion cell layer was increased at 3 months, and BACE1 expression in the ganglion cell layer, inner plexiform layer and outer plexiform layer was significantly increased at 6 and 8 months, compared with age-matched wild-type mice. Taken together, these results indicate that changes in BACE1 expression appear earlier in the retina than in the brain and precede behavioral deficits. Our findings suggest that abnormal expression of BACE1 in the retina is an early pathological change in APP/PS-1 transgenic mice, and that BACE1 might have potential as a biomarker for the early diagnosis of AD in humans.

Key words: nerve regeneration, neurodegenerative disease, Alzheimer’s disease, retina, amyloid-β, β-site amyloid precursor protein cleaving enzyme 1, APP/PS-1 transgenic mouse, neural regeneration