中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (11): 2381-2390.doi: 10.4103/1673-5374.335832

• 综述:退行性病与再生 • 上一篇    下一篇

用于临床前和临床阿尔茨海默病的新兴外泌体的血液生物标记物：荟萃分析和系统评价

  

  • 出版日期:2022-11-15 发布日期:2022-04-21

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer’s disease: a meta-analysis and systematic review

Wei-Lin Liu1, 2, #, Hua-Wei Lin1, #, Miao-Ran Lin3, Yan Yu3, Huan-Huan Liu1, Ya-Ling Dai3, Le-Wen Chen1, Wei-Wei Jia3, Xiao-Jun He1, Xiao-Ling Li3, Jing-Fang Zhu3, Xie-Hua Xue4, Jing Tao1, Li-Dian Chen1, *   

  1. 1Academy of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China; 2Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 3National-Local Joint Engineering Research Center of Rehabilitation Medicine Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China; 4Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China
  • Online:2022-11-15 Published:2022-04-21
  • Contact: Li-Dian Chen, PhD, cld@fjtcm.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China (Key Project), No. 82030123 (to LDC), the Science and Technology Platform Construction Project of Fujian Science and Technology Department, No. 2018Y2002 (to LDC).

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摘要：

血液来源的外泌体是一类由活细胞分泌到循环血液中的脂质双层包裹的细胞外囊泡，其被认为是一种相对无创的监测脑生理和疾病状态的新型标志物。越来越多的血液外泌体内含物质正在成为临床前和临床阿尔茨海默病的潜在生物标志物。因此，文章对源自血液外泌体的分子生物标志物进行了荟萃分析和系统评价，以综合分析它们在临床前阿尔茨海默病、轻度认知障碍和阿尔茨海默病中的诊断价值。(1)文章对PubMed，Web of Science，Embase和Cochrane Library数据库自建库至2020-08-15的文献进行了检索筛选，研究对象主要包括阿尔茨海默病、轻度认知障碍和临床前阿尔茨海默病患者。(2)文章共纳入34项观察性研究，其中15项最终纳入定量分析(NOS量表平均分为5.87分)，19项纳入定性分析。(3)Meta分析结果表明，在临床前阿尔茨海默病、轻度认知障碍和阿尔茨海默病患者的血液神经元来源外泌体中，包括Aβ1-42、P-T181-tau、P-S396-tau和T-tau在内的核心分子生物标志物水平显著增加(P < 0.05)。(4)涉及神经炎症(C1q)、代谢紊乱(P-S312-IRS-1)、神经营养缺乏(HGF)、血管损伤(VEGF-D)和自噬-溶酶体系统功能障碍(cathepsin D)其他危险因素的大多数相关分子表达水平也显著增加。(5)在基因层面，各组血液中转录相关因子(REST)和miRNA(miR-132)的差异表达也会影响RNA剪接、转运和翻译等过程。以上全部病理改变最终将导致神经元损失和突触功能障碍(neurogranin)。(6)上述数据证实，血液外泌体来源的核心分子(如Aβ1-42、P-T181-tau、P-S396-tau和T-tau)和其他与危险因素有关的因子，可以作为临床前和临床阿尔茨海默病的候选生物标志物，并且这些研究成果促使外泌体生物标志物的进一步开发，并逐渐应用于阿尔茨海默病的临床血液检测。该荟萃分析已在国际前瞻性系统评价登记处登记(注册号：CRD4200173498，2020-04-28)。

https://orcid.org/0000-0002-6454-7932 (Li-Dian Chen).

关键词: 阿尔茨海默病, 淀粉样β, 生物标记物, 血液, 外泌体, 细胞外囊泡, 荟萃分析, 轻度认知障碍, 系统评价, tau蛋白

Abstract: Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer’s disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer’s disease, mild cognitive impairment, and Alzheimer’s disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer’s disease, mild cognitive impairment, and preclinical Alzheimer’s disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aβ1–42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer’s disease, mild cognitive impairment, and Alzheimer’s disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer’s disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer’s disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

Key words: Alzheimer’s disease, amyloid-β, biomarkers, blood, exosomes, extracellular vesicles, meta-analysis, mild cognitive impairment, systematic review, tau protein