Aurore Delvenne, Charysse Vandendriessche, Johan Gobom, Marlies Burgelman, Pieter Dujardin, Clint De Nolf, Betty M Tijms, Charlotte E Teunissen, Suzanne E Schindler, Frans Verhey, Inez Ramakers, Pablo Martinez-Lage, Mikel Tainta, Rik Vandenberghe, Jolien Schaeverbeke, Sebastiaan Engelborghs, Ellen De Roeck, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Yvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Roosmarijn E Vandenbroucke, Stephanie J B Vos
{"title":"脉络丛在阿尔茨海默病病理生理学中的参与：小鼠和人类蛋白质组研究的发现。","authors":"Aurore Delvenne, Charysse Vandendriessche, Johan Gobom, Marlies Burgelman, Pieter Dujardin, Clint De Nolf, Betty M Tijms, Charlotte E Teunissen, Suzanne E Schindler, Frans Verhey, Inez Ramakers, Pablo Martinez-Lage, Mikel Tainta, Rik Vandenberghe, Jolien Schaeverbeke, Sebastiaan Engelborghs, Ellen De Roeck, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Yvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Roosmarijn E Vandenbroucke, Stephanie J B Vos","doi":"10.1186/s12987-024-00555-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>We used an APP knock-in mouse model, APP<sup>NL-G-F</sup>, 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.</p><p><strong>Results: </strong>ChP tissue proteome was dysregulated in APP<sup>NL-G-F</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"21 1","pages":"58"},"PeriodicalIF":5.9000,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256635/pdf/","citationCount":"0","resultStr":"{\"title\":\"Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies.\",\"authors\":\"Aurore Delvenne, Charysse Vandendriessche, Johan Gobom, Marlies Burgelman, Pieter Dujardin, Clint De Nolf, Betty M Tijms, Charlotte E Teunissen, Suzanne E Schindler, Frans Verhey, Inez Ramakers, Pablo Martinez-Lage, Mikel Tainta, Rik Vandenberghe, Jolien Schaeverbeke, Sebastiaan Engelborghs, Ellen De Roeck, Julius Popp, Gwendoline Peyratout, Magda Tsolaki, Yvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Roosmarijn E Vandenbroucke, Stephanie J B Vos\",\"doi\":\"10.1186/s12987-024-00555-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>We used an APP knock-in mouse model, APP<sup>NL-G-F</sup>, 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.</p><p><strong>Results: </strong>ChP tissue proteome was dysregulated in APP<sup>NL-G-F</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":12321,\"journal\":{\"name\":\"Fluids and Barriers of the CNS\",\"volume\":\"21 1\",\"pages\":\"58\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2024-07-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256635/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Fluids and Barriers of the CNS\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12987-024-00555-3\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Fluids and Barriers of the CNS","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12987-024-00555-3","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies.
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.
期刊介绍：
"Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease.
At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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