Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease
Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in...
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BMC
2025-05-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-025-00853-w |
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| author | Zhong-Jiang Yan Maosen Ye Jiexi Li Deng-Feng Zhang Yong-Gang Yao |
| author_facet | Zhong-Jiang Yan Maosen Ye Jiexi Li Deng-Feng Zhang Yong-Gang Yao |
| author_sort | Zhong-Jiang Yan |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression remain inadequately understood. Methods To elucidate the molecular abnormalities during the early stages of AD, we acquired single-cell transcription profiling of ChP from APP/PS1 mice with early-stage of Aβ pathology and litter-mate controls. The transcriptional alterations that occurred in each cell type were identified by differentially expressed genes, cell–cell communications and pseudotemporal trajectory analysis. The findings were subsequently validated by a series of in situ and in vitro assays. Results We constructed a comprehensive atlas of ChP at single-cell resolution and identified six major cell types and immune subclusters in male mice. The majority of dysregulated genes were found in the epithelial cells of APP/PS1 mice in comparison to wild-type (WT) mice, and most of these genes belonged to down-regulated module involved in mitochondrial respirasome assembly, cilium organization, and barrier integrity. The disruption of the epithelial barrier resulted in the downregulation of macrophage migration inhibitory factor (MIF) secretion in APP/PS1 mice, leading to macrophage activation and increased phagocytosis of Aβ. Concurrently, ligands (e.g., APOE) secreted by macrophages and other ChP cells facilitated the entry of lipids into ependymal cells, leading to lipid accumulation and the activation of microglia in the brain parenchyma in APP/PS1 mice compared to WT controls. Conclusions Taken together, these data profiled early transcriptional and cellular abnormalities of ChP within an AD mouse model, providing novel insights of cerebral vasculature into the pathobiology of AD. |
| format | Article |
| id | doaj-art-5b8a700b453e49d5bb56997eab9db51e |
| institution | OA Journals |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-5b8a700b453e49d5bb56997eab9db51e2025-08-20T02:00:08ZengBMCMolecular Neurodegeneration1750-13262025-05-0120112110.1186/s13024-025-00853-wEarly transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s diseaseZhong-Jiang Yan0Maosen Ye1Jiexi Li2Deng-Feng Zhang3Yong-Gang Yao4State Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Genetic Evolution & Animal Models, Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of SciencesAbstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression remain inadequately understood. Methods To elucidate the molecular abnormalities during the early stages of AD, we acquired single-cell transcription profiling of ChP from APP/PS1 mice with early-stage of Aβ pathology and litter-mate controls. The transcriptional alterations that occurred in each cell type were identified by differentially expressed genes, cell–cell communications and pseudotemporal trajectory analysis. The findings were subsequently validated by a series of in situ and in vitro assays. Results We constructed a comprehensive atlas of ChP at single-cell resolution and identified six major cell types and immune subclusters in male mice. The majority of dysregulated genes were found in the epithelial cells of APP/PS1 mice in comparison to wild-type (WT) mice, and most of these genes belonged to down-regulated module involved in mitochondrial respirasome assembly, cilium organization, and barrier integrity. The disruption of the epithelial barrier resulted in the downregulation of macrophage migration inhibitory factor (MIF) secretion in APP/PS1 mice, leading to macrophage activation and increased phagocytosis of Aβ. Concurrently, ligands (e.g., APOE) secreted by macrophages and other ChP cells facilitated the entry of lipids into ependymal cells, leading to lipid accumulation and the activation of microglia in the brain parenchyma in APP/PS1 mice compared to WT controls. Conclusions Taken together, these data profiled early transcriptional and cellular abnormalities of ChP within an AD mouse model, providing novel insights of cerebral vasculature into the pathobiology of AD.https://doi.org/10.1186/s13024-025-00853-wAlzheimer’s diseaseChoroid plexusSingle-cell transcriptomeLipid accumulationNeuroinflammation |
| spellingShingle | Zhong-Jiang Yan Maosen Ye Jiexi Li Deng-Feng Zhang Yong-Gang Yao Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease Molecular Neurodegeneration Alzheimer’s disease Choroid plexus Single-cell transcriptome Lipid accumulation Neuroinflammation |
| title | Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease |
| title_full | Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease |
| title_fullStr | Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease |
| title_full_unstemmed | Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease |
| title_short | Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease |
| title_sort | early transcriptional and cellular abnormalities in choroid plexus of a mouse model of alzheimer s disease |
| topic | Alzheimer’s disease Choroid plexus Single-cell transcriptome Lipid accumulation Neuroinflammation |
| url | https://doi.org/10.1186/s13024-025-00853-w |
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