Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody
Abstract Background Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (Tf...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13195-018-0377-8 |
| _version_ | 1828756979055591424 |
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| author | Stina Syvänen Greta Hultqvist Tobias Gustavsson Astrid Gumucio Hanna Laudon Linda Söderberg Martin Ingelsson Lars Lannfelt Dag Sehlin |
| author_facet | Stina Syvänen Greta Hultqvist Tobias Gustavsson Astrid Gumucio Hanna Laudon Linda Söderberg Martin Ingelsson Lars Lannfelt Dag Sehlin |
| author_sort | Stina Syvänen |
| collection | DOAJ |
| description | Abstract Background Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils. Methods Aβ protein precursor (AβPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aβ protofibrils and total Aβ in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography. Results ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aβ protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aβ protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aβ levels by different mechanisms. Conclusions With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs. |
| first_indexed | 2024-12-10T23:24:39Z |
| format | Article |
| id | doaj.art-f12a0b5f726a4f9cb0f180d2f407b2ee |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-10T23:24:39Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-f12a0b5f726a4f9cb0f180d2f407b2ee2022-12-22T01:29:37ZengBMCAlzheimer’s Research & Therapy1758-91932018-05-0110111010.1186/s13195-018-0377-8Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibodyStina Syvänen0Greta Hultqvist1Tobias Gustavsson2Astrid Gumucio3Hanna Laudon4Linda Söderberg5Martin Ingelsson6Lars Lannfelt7Dag Sehlin8Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryDepartment of Pharmaceutical biosciences, Uppsala UniversityDepartment of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryDepartment of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryBioArctic ABBioArctic ABDepartment of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryDepartment of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryDepartment of Public Health and Caring Sciences/Geriatrics, Uppsala University, Rudbeck LaboratoryAbstract Background Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer’s disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils. Methods Aβ protein precursor (AβPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aβ protofibrils and total Aβ in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography. Results ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aβ protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aβ protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aβ levels by different mechanisms. Conclusions With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.http://link.springer.com/article/10.1186/s13195-018-0377-8Alzheimer’s disease (AD)ImmunotherapyAmyloid-β (Aβ)OligomersProtofibrilsMonoclonal antibody |
| spellingShingle | Stina Syvänen Greta Hultqvist Tobias Gustavsson Astrid Gumucio Hanna Laudon Linda Söderberg Martin Ingelsson Lars Lannfelt Dag Sehlin Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody Alzheimer’s Research & Therapy Alzheimer’s disease (AD) Immunotherapy Amyloid-β (Aβ) Oligomers Protofibrils Monoclonal antibody |
| title | Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody |
| title_full | Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody |
| title_fullStr | Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody |
| title_full_unstemmed | Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody |
| title_short | Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody |
| title_sort | efficient clearance of aβ protofibrils in aβpp transgenic mice treated with a brain penetrating bifunctional antibody |
| topic | Alzheimer’s disease (AD) Immunotherapy Amyloid-β (Aβ) Oligomers Protofibrils Monoclonal antibody |
| url | http://link.springer.com/article/10.1186/s13195-018-0377-8 |
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