外泌体ABCA1蛋白在阿尔茨海默病诊断中的价值

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摘要目的通过小鼠实验和临床标本检测初步研究外泌体ATP结合盒转运体A1（ABCA1）蛋白作为阿尔茨海默病（AD）诊断标志物的价值。方法提取9月龄组APP/PS1 AD模型小鼠脑脊液（CSF）和血清外泌体分别进行质谱分析和ABCA1蛋白酶联免疫吸附试验（ELISA）检测。将3、6、9月龄组APP/PS1小鼠CSF外泌体注射至3月龄组野生型（WT）小鼠的第三脑室后分别检测0、2、4、6 h组血清和CSF外泌体ABCA1水平。检测69例主观认知下降（SCD）组、43例轻度认知障碍（MCI）组和35例痴呆期（DAT）组及30例对照组受试者的血清外泌体ABCA1水平。结果质谱和ELISA结果示：3、6、9月龄组APP/PS1双转基因小鼠CSF和血清外泌体ABCA1蛋白水平分别高于同月龄WT小鼠（P < 0.05）；6月龄组APP/PS1双转基因小鼠CSF和血清中外泌体ABCA1蛋白水平显著高于3月龄组APP/PS1双转基因小鼠（P < 0.05），9月龄组APP/PS1双转基因小鼠CSF和血清中外泌体ABCA1蛋白水平显著高于6月龄组APP/PS1双转基因小鼠（P < 0.05）。外泌体注射后2、4、6 h组的WT小鼠血清外泌体ABCA1蛋白水平显著升高（P < 0.05），4 h组最高；外泌体注射后2、4、6 h组的WT小鼠CSF外泌体ABCA1蛋白水平均显著降低（P < 0.05），6 h组最低。SCD组与对照组血清外泌体ABCA1蛋白水平比较差异无统计学意义（P > 0.05）；MCI组和DAT组血清外泌体ABCA1蛋白水平较对照组显著升高（P < 0.05），且DAT组显著高于MCI组（P < 0.05）。当截断值为0.39时，血清外泌体ABCA1蛋白诊断MCI的敏感度为72.5%，特异度为75.4%；当截断值为0.52时，血清外泌体ABCA1蛋白诊断DAT的敏感度为70.1%，特异度为69.2%；血清外泌体ABCA1对MCI和DAT的诊断效能显著高于SCD（P < 0.05）。结论 ABCA1蛋白外泌体可经透过血脑屏障到达外周血而被有效检测，其可作为AD诊断的候选标志物，但在SCD的诊断中还需积累更多的研究数据。

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	刘辰庚1 支杨2 李莹1
	3 赵越1 路尧1 王培昌1

关键词 ：阿尔茨海默病, 外泌体, 诊断, ATP结合盒转运体A1

Abstract：Objective To preliminary study the value of exosome ABCA1 protein as a diagnostic marker for Alzheimer′s disease (AD) through mouse experiments and clinical specimen detection. Methods Cerebrospinal fluid (CSF) and serum exosomes of APP/PS1 AD model mice in nine-month-old group were extracted and analyzed by mass spectrometry and ABCA1 protein detected by enzyme linked immunosorbent assay (ELISA). After three, six, nine months old APP/PS1 mice cerebrospinal fluid exosomes were injected into the third ventricle of three-month-old wild type (WT) mice, serum and CSF of zero, two, four, six-hour-groups were detected respectively exosome ABCA1 level. Serum exosome ABCA1 levels were detected in 69 patients with subjective cognitive decline (SCD group), 43 patients with mild cognitive impairment (MCI group) and 35 patients with dementia (DAT group) and 30 cases of control group. Results The results of mass spectrometry and ELISA showed that the levels of CSF and ABCA1 protein in serum of APP/PS1 double transgenic mice in three-month-old group, six-month-old group and nine-month-old group were higher than those of WT mice at the same month age (P < 0.05). CSF and serum exosomes ABCA1 protein of APP/PS1 double transgenic mice in six-month-old group were significantly higher than those in three-month-old group (P < 0.05). CSF and serum exosomes ABCA1 protein in nine-month-old APP/PS1 double transgenic mice were significantly higher than those in six-month-old APP/PS1 double transgenic mice (P < 0.05). The serum level of ABCA1 protein in WT mice was significantly increased in two, four and six hour-groups after exosomes injection (P < 0.05), and the highest level was found in four-hour group. The levels of ABCA1 protein in CSF exosomes of WT mice were significantly decreased in two, four and six hour-group after exosomes injection (P < 0.05), and the lowest in six-hour-group. There was no significant difference in ABCA1 protein between SCD group and control group (P > 0.05). The level of ABCA1 protein in serum of MCI group and DAT group was significantly higher than that of control group (P < 0.05), and that of DAT group was significantly higher than that of MCI group (P < 0.05). When the cut-off value was 0.39, the sensitivity and specificity of ABCA1 protein was 72.5% and 75.4% respectively, when the cut-off value was 0.52, the sensitivity and specificity of ABCA1 protein was 70.1% and 69.2% respectively in the diagnose of MCI. The diagnostic efficiency of ABCA1 protein in MCI and DAT was significantly higher than that in SCD (P < 0.05). Conclusion ABCA1 exosomes can pass through the blood-brain barrier and reach the peripheral blood, which can be used as a candidate marker for AD diagnosis. However, more research data need to be accumulated in the diagnosis of SCD.

Key words： Alzheimer′s disease Exosome Diagnosis ATP-binding cassette transporter A1

基金资助:国家自然科学基金资助项目（81401734、814720 07）。

通讯作者: 王培昌（1965-），男，主任技师，教授，博士生导师；研究方向：衰老和相关疾病机制研究及标志物筛选。

作者简介: 刘辰庚（1980-），男，博士，副主任技师，副教授，硕士生导师；研究方向：衰老和相关疾病标志物筛选。

引用本文:

刘辰庚1 支杨2 李莹1，3 赵越1 路尧1 王培昌1. 外泌体ABCA1蛋白在阿尔茨海默病诊断中的价值[J]. 中国医药导报, 2020, 17(28): 6-9,13.
LIU Chengeng1 ZHI Yang2 LI Ying1,3 ZHAO Yue1 LU Yao1 WANG Peichang1. The value of exosomal ABCA1 protein in the diagnosis of Alzheimer′s disease. 中国医药导报, 2020, 17(28): 6-9,13.

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