Sun Jianru, Shao Xiangqi, Wang Xue, Yin Xiang-Sha, Qiu Wenying, Qian Xiaojing, Liu Fan, Chen Yongmei, Ma Chao
Department of Human Anatomy, Histology and Embryology, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, No. 5 Dongdansantiao, Dongcheng District, Beijing, 100005, P. R. China.
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.
Mol Brain. 2025 Jun 22;18(1):53. doi: 10.1186/s13041-025-01226-6.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of pathological techniques and analysis of the human brain database, we discovered that focal Aβ plaques (FAPs), rather than diffuse Aβ plaques (DAPs), are significantly correlated with AD-related neuropathological changes and cognitive impairment. By using laser capture microdissection in conjunction with microproteomics, the protein components of different Aβ plaques were characterized. Bioinformatic analysis indicated that FAP-enriched proteins are associated mainly with immune-related pathways, such as neutrophil extracellular trap formation. We further confirmed that myeloperoxidase (MPO) is significantly upregulated in the AD brain and colocalizes with FAPs but not with DAPs. Immunohistochemical staining demonstrated that neutrophils expressing MPO accumulated in the capillary lumen and brain parenchyma. The number of neutrophils significantly increases in the cortex and hippocampus of AD donors. Our study revealed a potential role for neutrophil-derived MPO in FAPs, providing insights into the pathogenesis mechanisms and potential therapeutic targets of AD.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病。不同类型的β淀粉样蛋白（Aβ）斑块可能在AD患者的大脑中发挥不同作用。在本研究中，通过结合病理技术和对人脑数据库的分析，我们发现局灶性Aβ斑块（FAPs）而非弥漫性Aβ斑块（DAPs）与AD相关神经病理变化和认知障碍显著相关。通过将激光捕获显微切割与微蛋白质组学相结合，对不同Aβ斑块的蛋白质成分进行了表征。生物信息学分析表明，富含FAP的蛋白质主要与免疫相关途径有关，如中性粒细胞胞外陷阱形成。我们进一步证实，髓过氧化物酶（MPO）在AD大脑中显著上调，且与FAPs共定位，但不与DAPs共定位。免疫组织化学染色显示，表达MPO的中性粒细胞积聚在毛细血管腔和脑实质中。AD供体的皮质和海马中中性粒细胞数量显著增加。我们的研究揭示了中性粒细胞衍生的MPO在FAPs中的潜在作用，为AD的发病机制和潜在治疗靶点提供了见解。
