中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (2): 569-576.doi: 10.4103/NRR.NRR-D-24-00695

• 综述:退行性病与再生 • 上一篇    下一篇

正常衰老和阿尔茨海默病中脑内皮细胞转录组的异质性

  

  • 出版日期:2026-02-15 发布日期:2025-05-22

Insights into the transcriptomic heterogeneity of brain endothelial cells in normal aging and Alzheimer’s disease

Qian Yue1, 2, 3, 4, Shang Li5 , Chon Lok Lei6 , Huaibin Wan1, *, Zaijun Zhang7, 8, 9, *, Maggie Pui Man Hoi3, 4, *   

  1. 1 The Fifth Affiliated Hospital of Jinan University (Heyuan Shenhe People’s Hospital), Heyuan, Guangdong Province, China;  2 Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China;  3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao Special Administrative Region, China;  4 Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao Special Administrative Region, China;  5 Laboratory for Accelerated Vascular Research, Department of Surgery, University of California San Francisco, San Francisco, CA, USA;  6 Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macao Special Administrative Region, China;  7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, and Institute of New Drug Research, Jinan University, Guangzhou, Guangdong Province, China;  8 Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University College of Pharmacy, Guangzhou, Guangdong Province, China;  9 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou, Guangdong Province, China
  • Online:2026-02-15 Published:2025-05-22
  • Contact: Maggie Pui Man Hoi, PhD, maghoi@um.edu.mo; Huaibin Wan, PhD, docvanhb@outlook.com; Zaijun Zhang, PhD, zaijunzhang@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82404892 (to QY), 82061160374 (to ZZ); the Science and Technology Development Fund, Macao Special Administrative Region, China, Nos. 0023/2020/AFJ, 0035/2020/AGJ; the University of Macau Research Grant, Nos. MYRG2022-00248- ICMS, MYRG-CRG2022-00010-ICMS (to MPMH); the Natural Science Foundation of Guangdong Province, No. 2024A1515012818 (to ZZ); and the Fundamental Research Funds for the Central Universities, No. 21623114 (to ZZ).

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摘要：

淀粉样β蛋白靶向疗法屡遭失败，围绕淀粉样β蛋白级联假说的争议不断，这些都表明阿尔茨海默病的药物开发极具挑战性。最近，抗淀粉样β蛋白单克隆抗体莱卡尼单抗（Lecanemab）的研发取得了进展，在 III 期临床试验（Clarity Alzheimer's disease）中，莱卡尼单抗在减轻早期阿尔茨海默病患者大脑淀粉样蛋白负荷和减缓认知能力下降方面取得了积极成果。尽管结果令人鼓舞，但淀粉样蛋白相关成像异常（ARIA）等副作用可能会限制其使用。ARIA可表现为ARIA-E（脑水肿或渗出）和ARIA-H（微出血或浅层淤血），据认为是由于炎症反应导致血管通透性增加，从而导致血液制品和富含蛋白质的液体渗漏到脑实质中。内皮功能障碍是阿尔茨海默病的早期病理特征。随着病情的发展，血脑屏障的渗漏会越来越严重。此外，阿尔茨海默病最强的遗传风险因素 APOE4 与较高的血管淀粉样蛋白负荷、ARIA 发生率增加和血脑屏障加速破坏有关。这些相互关联的血管异常突显了血管对阿尔茨海默病病理生理学的重要作用。此文章总结了最近脑内皮细胞异质性的评估研究，分析不同脑区微血管中脑内皮细胞的异质性及其与阿尔茨海默病进展的关系。

https://orcid.org/0000-0003-2630-3707 (Maggie Pui Man Hoi); https://orcid.org/0000-0001-7962-0939 (Huaibin Wan); https://orcid.org/0000-0002-0690-1673 (Zaijun Zhang)

关键词: 阿尔茨海默病, 脑微血管内皮细胞, 转录组异质性, 内皮细胞活化, 血脑屏障损伤, 神经血管细胞间通讯

Abstract: Drug development for Alzheimer’s disease is extremely challenging, as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-β cascade hypothesis. More recently, advances in the development of Lecanemab, an anti-amyloid-β monoclonal antibody, have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase III clinical trial (Clarity Alzheimer’s disease). Despite these promising results, side effects such as amyloid-related imaging abnormalities (ARIA) may limit its usage. ARIA can manifest as ARIA-E (cerebral edema or effusions) and ARIA-H (microhemorrhages or superficial siderosis) and is thought to be caused by increased vascular permeability due to inflammatory responses, leading to leakages of blood products and protein-rich fluid into brain parenchyma. Endothelial dysfunction is an early pathological feature of Alzheimer’s disease, and the blood–brain barrier becomes increasingly leaky as the disease progresses. In addition, APOE4, the strongest genetic risk factor for Alzheimer’s disease, is associated with higher vascular amyloid burden, increased ARIA incidence, and accelerated blood–brain barrier disruptions. These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease. Here, we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.

Key words: Alzheimer’s disease, brain microvessel endothelial cells, transcriptomic heterogeneity, endothelial activation, blood–brain barrier impairment, neurovascular cell–cell communication