Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model
Abstract Blood-brain barrier (BBB) dysfunction is an early pathological hallmark of Alzheimer’s disease (AD), occurring prior to amyloid-β (Aβ) accumulation. A key factor contributing to BBB damage in AD is the loss of endothelial expression of low-density lipoprotein receptor-related protein 1 (LRP...
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BMC
2025-08-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01840-5 |
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| author | Ting-Ting Pan Yan-Yun Sun Yi-Fan Shi Mei Zhao Naveed Ullah Khan Hai-Yan Chen Wen-Li Ji Jie Li Liang Han Quan-Hong Ma |
| author_facet | Ting-Ting Pan Yan-Yun Sun Yi-Fan Shi Mei Zhao Naveed Ullah Khan Hai-Yan Chen Wen-Li Ji Jie Li Liang Han Quan-Hong Ma |
| author_sort | Ting-Ting Pan |
| collection | DOAJ |
| description | Abstract Blood-brain barrier (BBB) dysfunction is an early pathological hallmark of Alzheimer’s disease (AD), occurring prior to amyloid-β (Aβ) accumulation. A key factor contributing to BBB damage in AD is the loss of endothelial expression of low-density lipoprotein receptor-related protein 1 (LRP1). Endothelial LRP1 is crucial for maintaining BBB integrity and facilitating the transcytosis of Aβ across the BBB for peripheral clearance. However, LRP1 is also expressed in other neural cell types, such as neurons, where it paradoxically promotes Aβ generation and tau propagation. These dual roles of LRP1 for different cell types present a challenge for developing effective AD therapy targeting LRP1. Simvastatin (SIM), an HMG-CoA reductase inhibitor, has been shown to induce compensatory upregulation of LRP1 expression. To harness this potential, we designed SIM-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) that can be effectively internalized by endothelial cells. Our findings demonstrate that intravenous (IV) injection with S@A-NPs upregulates endothelial LRP1 expression level, repairs BBB damage, attenuates Aβ accumulation, mitigates neurodegeneration, and ultimately preserves cognitive function in APP/PS1 mice. These results highlight the potential of endothelial delivery of SIM via nanoparticles to attenuate AD pathogenesis. Our study proposes a novel therapeutic strategy for AD by leveraging nanoparticle-mediated drug delivery. |
| format | Article |
| id | doaj-art-3b8d9ba4d19e4dce8c0228a8fbe2618d |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-3b8d9ba4d19e4dce8c0228a8fbe2618d2025-08-24T11:12:01ZengBMCAlzheimer’s Research & Therapy1758-91932025-08-0117112410.1186/s13195-025-01840-5Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse modelTing-Ting Pan0Yan-Yun Sun1Yi-Fan Shi2Mei Zhao3Naveed Ullah Khan4Hai-Yan Chen5Wen-Li Ji6Jie Li7Liang Han8Quan-Hong Ma9Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow UniversityDepartment of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow UniversityDepartment of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow UniversityJiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases and College of Pharmaceutical Sciences, Soochow UniversityJiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases and College of Pharmaceutical Sciences, Soochow UniversityJiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases and College of Pharmaceutical Sciences, Soochow UniversityDepartment of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow UniversityDepartment of General Practice, The First Affiliated Hospital of Soochow University, Soochow UniversityJiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho- Diseases and College of Pharmaceutical Sciences, Soochow UniversityDepartment of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow UniversityAbstract Blood-brain barrier (BBB) dysfunction is an early pathological hallmark of Alzheimer’s disease (AD), occurring prior to amyloid-β (Aβ) accumulation. A key factor contributing to BBB damage in AD is the loss of endothelial expression of low-density lipoprotein receptor-related protein 1 (LRP1). Endothelial LRP1 is crucial for maintaining BBB integrity and facilitating the transcytosis of Aβ across the BBB for peripheral clearance. However, LRP1 is also expressed in other neural cell types, such as neurons, where it paradoxically promotes Aβ generation and tau propagation. These dual roles of LRP1 for different cell types present a challenge for developing effective AD therapy targeting LRP1. Simvastatin (SIM), an HMG-CoA reductase inhibitor, has been shown to induce compensatory upregulation of LRP1 expression. To harness this potential, we designed SIM-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) that can be effectively internalized by endothelial cells. Our findings demonstrate that intravenous (IV) injection with S@A-NPs upregulates endothelial LRP1 expression level, repairs BBB damage, attenuates Aβ accumulation, mitigates neurodegeneration, and ultimately preserves cognitive function in APP/PS1 mice. These results highlight the potential of endothelial delivery of SIM via nanoparticles to attenuate AD pathogenesis. Our study proposes a novel therapeutic strategy for AD by leveraging nanoparticle-mediated drug delivery.https://doi.org/10.1186/s13195-025-01840-5SimvastatinNanoparticlesAlzheimer’s diseaseLRP1BBBAmyloid-β |
| spellingShingle | Ting-Ting Pan Yan-Yun Sun Yi-Fan Shi Mei Zhao Naveed Ullah Khan Hai-Yan Chen Wen-Li Ji Jie Li Liang Han Quan-Hong Ma Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model Alzheimer’s Research & Therapy Simvastatin Nanoparticles Alzheimer’s disease LRP1 BBB Amyloid-β |
| title | Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model |
| title_full | Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model |
| title_fullStr | Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model |
| title_full_unstemmed | Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model |
| title_short | Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer’s disease in a mouse model |
| title_sort | endothelial delivery of simvastatin by lrp1 targeted nanoparticles ameliorates pathogenesis of alzheimer s disease in a mouse model |
| topic | Simvastatin Nanoparticles Alzheimer’s disease LRP1 BBB Amyloid-β |
| url | https://doi.org/10.1186/s13195-025-01840-5 |
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