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 (6): 2433-2439.doi: 10.4103/NRR.NRR-D-24-01287

• 原著:退行性病与再生 • 上一篇    下一篇

阿尔茨海默病患者血清改变体外小胶质细胞的吞噬功能

  

  • 出版日期:2026-06-15 发布日期:2026-04-17

Blood serum from individuals with Alzheimer’s disease alters microglial phagocytosis in vitro

Barbara Altendorfer1, Rodolphe Poupardin2, Sophie Lefèvre-Arbogast3, Claudine Manach4, Dorrain Y. Low4, Mireia Urpi-Sarda5, Cristina Andres-Lacueva5, Raúl González-Domínguez5, Thomas K. Felder6, 7, Julia Tevini6, Marco Zattoni1, Andreas Koller8, Reinhold Schmidt9, Paul J. Lucassen10, Silvie R. Ruigrok10, 11, Chiara de Lucia12, Andrea Du Preez12, Catherine Helmer3, Jeanne Neuffer3, Cécile Proust-Lima3, Aniko Korosi10, Cécilia Samieri3, Sandrine Thuret12, 13, Ludwig Aigner1, 14, *   

  1. 1Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; 
    2Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria; 
    3University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Bordeaux, France; 
    4Université Clermont Auvergne, INRAE, UMR1019, Human Nutrition Unit, Clermont Ferrand, France; 
    5Nutrition, Food Science and Gastronomy Department, Faculty of Pharmacy and Food Science, Nutrition and Food Safety Research Institute (INSA), CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain; 
    6Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria; 
    7Institute of Pharmacy, Paracelsus Medical University, Salzburg, Austria; 
    8Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University, Salzburg, Austria; 
    9Department of Neurology, Medical University of Graz, Graz, Austria; 
    10Brain Plasticity Group, Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, Netherlands; 
    11École Polytechnique Fédérale de Lausanne - Brain Mind Institute - Laboratory of Behavioral Genetics, Lausanne, Switzerland; 
    12Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; 
    13Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 
    14Austrian Cluster of Tissue Regeneration, Vienna, Austria
  • Online:2026-06-15 Published:2026-04-17
  • Contact: Ludwig Aigner, PhD, ludwig.aigner@pmu.ac.at.
  • Supported by:
    This study was part of the EU consortium DCogPlast ‘Diet Cognition and Plasticity” funded by the Joint Programming Initiative “A Health Diet for a Healthy Life” (JPI-HDHL) via the BMWFW (BMWFW-10.420/0009-WF/V/3c/2015 and the Medical Research Council UK:  R/N030087/1) (to LA and ST). Further, LA was supported by the PMU-FFF Research Fund (A-16/01/019-AIG) and BA by the PMU-Research and Innovation Fund (PMU-RIF) (project 2023-PRE-008-Altendorfer). PJL was supported by the Center for Urban Mental Health, and AK and PJL by Alzheimer Nederland and the ZonMW Program Mechanisms Of DEMentia (MODEM) and by the Gravitation program iCNS of the Dutch Research Council (NWO). CAL was supported by Grant PID2020-114921RB-C21, Maria de Maeztu Unit of Excellence grant CEX2021-001234-M funded by MCIU/AEI/ and CIBERFES, CB16/10/00269, from the Instituto de Salud Carlos III all of them by “ERDF A way of making Europe”, the Generalitat de Catalunya’s Agency AGAUR of 2021SGR00687 and ICREA Award.

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摘要：

在阿尔茨海默病的发病过程中，小胶质细胞的吞噬作用参与了发病机制，因为它在疾病的早期阶段能清除异常的蛋白质积聚、碎屑和凋亡细胞，但在晚期阶段会助长神经炎症并加速疾病的发展。对老年动物进行的体内同种异体移植实验表明，血液中的因子可调节突触可塑性、神经发生和小胶质细胞反应。实验假设，外周因子可以调节小胶质细胞的功能，从而可能影响阿尔茨海默病的病理表现。为探讨阿尔茨海默病血清对小胶质细胞吞噬功能的影响，实验使用永生化的人类小胶质细胞系，观察来源于PRODEM 研究的阿尔茨海默病患者（30 例）和年龄匹配的对照组（30 例）的血清对小胶质细胞吞噬功能的影响。结果发现，暴露于阿尔茨海默病血清会增加小胶质细胞对pH敏感荧光颗粒的吞噬摄取，并下调溶酶体主调节因子转录因子EB（TFEB）和空泡ATP酶的一个组成部分--ATP酶H+转运溶酶体V1亚基B2（ATP6V1B2）的表达。为了确定可能与吞噬作用变化有关的血清成分，使用了三城市研究（3C 研究）的血清样本。在 3C 研究中，血液样本是在认知能力下降或痴呆症发病前 12 年采集的，其血清代谢组已明确定义。与匹配的对照组血清相比，暴露于3C研究中未来阿尔茨海默病病例血清的小胶质细胞显示出更高的吞噬吸收率，这取决于阿尔茨海默病病例中是否存在载脂蛋白E ε4等位基因（ApoE4）。此外，小胶质细胞的吞噬作用与血清中omega 3 脂肪酸二十碳五烯酸（EPA）的水平成反比。实验在 PRODEM人群血清样本中证实了 EPA 与吞噬作用之间的反相关性。此外，EPA 对小胶质细胞吞噬能力的体外测试表明，吞噬细胞摄取量呈浓度依赖性下降。总之，在与培养于阿尔茨海默病血清后，小胶质细胞吞噬摄取增加，TFEB 和 ATP6V1B2 下调，这可能表明溶酶体功能障碍。此外，小胶质细胞的吞噬作用与血清中 EPA 的水平成反比，这表明膳食中的 EPA 在小胶质细胞功能中发挥着重要作用。


https://orcid.org/0000-0002-1653-8046 (Ludwig Aigner)

关键词: EPA, 阿尔茨海默病, 血清, 二十碳五烯酸, 代谢组, 小胶质细胞, ω-3脂肪酸, 吞噬作用

Abstract: In Alzheimer’s disease, microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of Alzheimer’s disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis, and microglial responses. We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer’s disease pathology. The objective of this study is to investigate the effects of Alzheimer’s disease serum on microglial phagocytosis. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer’s disease (n = 30) and age-matched controls (n = 30) (PRODEM study) on microglial phagocytosis. Exposure to Alzheimer’s disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB (TFEB) and of ATPase H+ transporting lysosomal V1 subunit B2 (ATP6V1B2), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to the serum of future Alzheimer’s disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls, depending on the presence of the apolipoprotein E ε4 allele in the Alzheimer’s disease patients. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid. We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with Alzheimer’s disease blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2, possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels, suggesting an important role for dietary eicosapentaenoic acid in microglial function.

Key words: Alzheimer’s disease, blood serum, eicosapentaenoic acid, in vitro parabiosis, metabolome, microglia, omega-3 fatty acids, phagocytosis