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Abstract：
BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer\'s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.
METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD.
RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways.
CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.
METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD.
RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways.
CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.
摘要：
背景：在阿尔茨海默病（AD）中已经报道了脉络丛（ChP）的结构和功能变化。尽管如此，ChP在AD发病机制中的作用尚不清楚。我们的目标是在小鼠和人类中使用独特的蛋白质组学方法来阐明ChP功能与核心AD发病机理之间的关系。
方法：我们使用了APP敲入小鼠模型，APPNL-G-F,表现出淀粉样蛋白病理学，利用液相色谱-质谱联用技术研究AD脑病理与小鼠ChP组织和CSF蛋白变化的相关性。在7周龄(n=5)和40周龄(n=5)研究小鼠蛋白质组。将结果与先前发表的人ADCSF蛋白质组数据(n=496)进行比较,以鉴定与AD中ChP变化相关的关键蛋白和途径。
结果:在APPNL-G-F小鼠中,在7周和40周时,ChP组织蛋白质组相对于野生型小鼠失调。在两个年龄段，ChP组织蛋白质组改变与上皮细胞相关,线粒体,蛋白质修饰，细胞外基质和脂质。尽管如此，一些ChP组织蛋白质组变化在整个疾病轨迹上是不同的；与溶酶体功能相关的途径，内吞作用,蛋白质形成，肌动蛋白和补体在7周时独特地失调，而与神经系统相关的通路，免疫系统,蛋白质降解和血管系统在40周时出现独特的失调.小鼠和人类的CSF蛋白质组学显示出相似的ChP相关失调途径。
结论：一起，我们的研究结果支持AD患者ChP功能障碍的假设.这些ChP变化与淀粉样蛋白病理有关。因此,ChP可能成为新的有希望的AD治疗靶点。
方法：我们使用了APP敲入小鼠模型，APPNL-G-F,表现出淀粉样蛋白病理学，利用液相色谱-质谱联用技术研究AD脑病理与小鼠ChP组织和CSF蛋白变化的相关性。在7周龄(n=5)和40周龄(n=5)研究小鼠蛋白质组。将结果与先前发表的人ADCSF蛋白质组数据(n=496)进行比较,以鉴定与AD中ChP变化相关的关键蛋白和途径。
结果:在APPNL-G-F小鼠中,在7周和40周时,ChP组织蛋白质组相对于野生型小鼠失调。在两个年龄段，ChP组织蛋白质组改变与上皮细胞相关,线粒体,蛋白质修饰，细胞外基质和脂质。尽管如此，一些ChP组织蛋白质组变化在整个疾病轨迹上是不同的；与溶酶体功能相关的途径，内吞作用,蛋白质形成，肌动蛋白和补体在7周时独特地失调，而与神经系统相关的通路，免疫系统,蛋白质降解和血管系统在40周时出现独特的失调.小鼠和人类的CSF蛋白质组学显示出相似的ChP相关失调途径。
结论：一起，我们的研究结果支持AD患者ChP功能障碍的假设.这些ChP变化与淀粉样蛋白病理有关。因此,ChP可能成为新的有希望的AD治疗靶点。
