中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (12): 3574-3590.doi: 10.4103/NRR.NRR-D-24-00865

• 原著:退行性病与再生 • 上一篇    下一篇

从大脑到外周的 Aβ 清除相关蛋白的系统综述：对阿尔茨海默病诊断和治疗目标的影响

  

  • 出版日期:2025-12-15 发布日期:2025-03-17
  • 基金资助:
    国家自然科学基金(81571046号)、辽宁省教育厅重点项目(LJKZ0755号)、辽宁省科技厅项目(2023JH2/20200116号)、沈阳市中青年创新人才支持计划(RC210240号)、中国医科大学附属盛京医院345人才项目。

Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets

Letian Huang1 , Mingyue Liu2 , Ze Li2 , Bing Li2 , Jiahe Wang3, *, Ke Zhang2, *   

  1. 1 Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China;  2 Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, Liaoning Province, China;  3 Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2025-12-15 Published:2025-03-17
  • Contact: Ke Zhang, PhD, kzhang@cmu.edu.cn; Jiahe Wang, PhD, wangjh1@sj-hospital.org.
  • About author:
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81571046 (to KZ); Key Project of Educational Department of Liaoning Province, No. LJKZ0755 (to KZ); Project of Department of Science & Technology of Liaoning Province, No. 2023JH2/20200116 (to KZ); Shenyang Young and Middleaged Innovative Talents Support Program, No. RC210240 (to KZ); and the 345 Talent Project of Shengjing Hospital of China Medical University (to LH).

PDF

58

摘要：

β淀粉样蛋白(Aβ)清除在阿尔茨海默病发病机制中起着关键作用。然而，参与β淀粉样蛋白清除的功能蛋白的变化及其与β淀粉样蛋白水平的相关性仍不清楚。文章检索了PubMed、Embase、Web of Science和Cochrane图书馆数据库中的文献进行了荟萃分析和系统综述，包括从开始到2023-06-30发表的研究类文章。纳入标准包括比较健康对照组、轻度认知障碍和阿尔茨海默病患者血液、脑脊液和大脑中β淀粉样蛋白清除功能蛋白水平的研究。此外，研究还评估了阿尔茨海默病患者体内功能蛋白与β淀粉样蛋白水平之间的相关性。研究的方法学质量采用纽卡斯尔-渥太华量表进行评估。根据异质性，采用固定或随机效应模型评估对照组和干预组之间标准均值差异(SMD)的95%置信区间(CI)。研究结果显示，阿尔茨海默病患者、轻度认知障碍患者和健康老年人群的大脑中的胰岛素降解酶、NEP、基质金属蛋白酶9、chepsin D、晚期糖基化终末产物受体(RAGE)和P-糖蛋白水平发生了明显变化。在脑脊液中，髓系细胞触发受体2(TREM2)和泛素羧基端水解酶L1(UCHL-1)的水平发生了变化，而在外周血中，TREM2、CD40、CD40L、CD14、CD22、chepsin D、胱抑素C和α2M的水平也有所不同。值得注意的是，TREM2和cathepsin D在大脑中都出现了显著性变化(SMD = 0.31，95% CI: = 0.16-0.47，P < 0.001，I2 = 78.4%；SMD = 1.24，95% CI：0.01-2.48，P = 0. 048，I2 = 90.1%)和外周血样本(SMD = 1.01，95% CI: = 0.35-1.66，P = 0.003，I2 = 96.5%；SMD = 7.55，95% CI: = 3.92-11.18，P < 0.001，I2 = 98.2%)。此外，在阿尔茨海默病患者中观察到Aβ水平与TREM2(r = 0.16，95% CI: = 0.04-0.28，P = 0.009，I2 = 74.7%)、NEP(r = -0.47，95% CI: = -0.8--0.14，P = 0.005，I2 = 76.1%)和P-糖蛋白(r = -0.31，95% CI: = -0.51--0.11，P = 0.002，I2 = 0.0%)水平之间存在相关性。上述结果数据显示，TREM2和cathepsin D可作为阿尔茨海默病的潜在诊断生物标志物，而TREM2、NEP和P-糖蛋白可作为潜在的治疗干预靶点。

https://orcid.org/0000-0003-3133-759X (Ke Zhang); https://orcid.org/0000-0001-6206-8404 (Jiahe Wang)

关键词: 阿尔茨海默病, β淀粉样蛋白, 血脑屏障, 脑脊液, 诊断生物标志物, 荟萃分析, 轻度认知障碍, 外周血, 系统综述, 治疗靶标

Abstract: Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer’s disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer’s disease. The methodological quality of the studies was assessed via the Newcastle‒Ottawa Scale. Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer’s disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16–0.47, P < 0.001, I 2 = 78.4%; SMD = 1.24, 95% CI: 0.01–2.48, P = 0.048, I 2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35–1.66, P = 0.003, I 2 = 96.5%; SMD = 7.55, 95% CI: 3.92–11.18, P < 0.001, I 2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (r = 0.16, 95% CI: 0.04–0.28, P = 0.009, I 2 = 74.7%), neprilysin (r = –0.47, 95% CI: –0.80–0.14, P = 0.005, I 2 = 76.1%), and P-glycoprotein (r = –0.31, 95% CI: –0.51–0.11, P = 0.002, I 2 = 0.0%) in patients with Alzheimer’s disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer’s disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.

Key words: Alzheimer’s disease, amyloid-β, blood?brain barrier, cerebrospinal fluid, diagnostic biomarker, meta-analysis, mild cognitive impairment, peripheral blood, systematic review, therapeutic targets