ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
Abstract Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44319-3 |
| _version_ | 1797209254620299264 |
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| author | Jiyeon Lee Haeryung Lee Hyein Lee Miram Shin Min-Gi Shin Jinsoo Seo Eun Jeong Lee Sun Ah Park Soochul Park |
| author_facet | Jiyeon Lee Haeryung Lee Hyein Lee Miram Shin Min-Gi Shin Jinsoo Seo Eun Jeong Lee Sun Ah Park Soochul Park |
| author_sort | Jiyeon Lee |
| collection | DOAJ |
| description | Abstract Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer’s disease mouse model results in exacerbated Aβ pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aβ clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aβ clearance across the BBB. |
| first_indexed | 2024-03-08T19:45:03Z |
| format | Article |
| id | doaj.art-0a4db409964d47408189638e17acd203 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T09:51:47Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0a4db409964d47408189638e17acd2032024-04-14T11:20:15ZengNature PortfolioNature Communications2041-17232023-12-0114112010.1038/s41467-023-44319-3ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cellsJiyeon Lee0Haeryung Lee1Hyein Lee2Miram Shin3Min-Gi Shin4Jinsoo Seo5Eun Jeong Lee6Sun Ah Park7Soochul Park8Department of Biological Sciences, Sookmyung Women’s UniversityDepartment of Biological Sciences, Sookmyung Women’s UniversityDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST)Department of Biological Sciences, Sookmyung Women’s UniversityDepartment of Brain Science, Ajou University School of MedicineDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST)Department of Brain Science, Ajou University School of MedicineLab for Neurodegenerative Dementia, Department of Anatomy, and Department of Neurology, Ajou University School of MedicineDepartment of Biological Sciences, Sookmyung Women’s UniversityAbstract Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer’s disease mouse model results in exacerbated Aβ pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aβ clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aβ clearance across the BBB.https://doi.org/10.1038/s41467-023-44319-3 |
| spellingShingle | Jiyeon Lee Haeryung Lee Hyein Lee Miram Shin Min-Gi Shin Jinsoo Seo Eun Jeong Lee Sun Ah Park Soochul Park ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells Nature Communications |
| title | ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells |
| title_full | ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells |
| title_fullStr | ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells |
| title_full_unstemmed | ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells |
| title_short | ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells |
| title_sort | anks1a regulates ldl receptor related protein 1 lrp1 mediated cerebrovascular clearance in brain endothelial cells |
| url | https://doi.org/10.1038/s41467-023-44319-3 |
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