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Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice
BACKGROUND: Alzheimer’s disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436657/ https://www.ncbi.nlm.nih.gov/pubmed/37596686 http://dx.doi.org/10.1186/s13195-023-01282-x |
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author | Tambaro, Simone Mitra, Sumonto Gera, Ruchi Linderoth, Bengt Wahlberg, Lars U. Darreh-Shori, Taher Behbahani, Homira Nilsson, Per Eriksdotter, Maria |
author_facet | Tambaro, Simone Mitra, Sumonto Gera, Ruchi Linderoth, Bengt Wahlberg, Lars U. Darreh-Shori, Taher Behbahani, Homira Nilsson, Per Eriksdotter, Maria |
author_sort | Tambaro, Simone |
collection | PubMed |
description | BACKGROUND: Alzheimer’s disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App(NL−G−F)). METHODS: ECB’s containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App(NL−G−F) mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings. RESULTS: The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. CONCLUSIONS: The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01282-x. |
format | Online Article Text |
id | pubmed-10436657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-104366572023-08-19 Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice Tambaro, Simone Mitra, Sumonto Gera, Ruchi Linderoth, Bengt Wahlberg, Lars U. Darreh-Shori, Taher Behbahani, Homira Nilsson, Per Eriksdotter, Maria Alzheimers Res Ther Research BACKGROUND: Alzheimer’s disease (AD) is an age-related disease characterized by altered cognition, neuroinflammation, and neurodegeneration against which there is presently no effective cure. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain penetration. In this study, we used an innovative encapsulated cell biodelivery (ECB) device, containing genetically modified cells capable of releasing BDNF and characterized its feasibility and therapeutic effects in the novel App knock-in AD mouse model (App(NL−G−F)). METHODS: ECB’s containing human ARPE-19 cells genetically modified to release BDNF (ECB-BDNF devices) were stereotactically implanted bilaterally into hippocampus of 3-month-old App(NL−G−F) mice. The stability of BDNF release and its effect on AD pathology were evaluated after 1, 2-, and 4-months post-implantation by immunohistochemical and biochemical analyses. Exploratory and memory performance using elevated plus maze (EPM) and Y-maze test were performed in the 4-months treatment group. Immunological reaction towards ECB-BDNF devices were studied under ex vivo and in vivo settings. RESULTS: The surgery and the ECB-BDNF implants were well tolerated without any signs of unwanted side effects or weight loss. ECB-BDNF devices did not induce host-mediated immune response under ex vivo set-up but showed reduced immune cell attachment when explanted 4-months post-implantation. Elevated BDNF staining around ECB-BDNF device proximity was detected after 1, 2, and 4 months treatment, but the retrieved devices showed variable BDNF release. A reduction of amyloid-β (Aβ) plaque deposition was observed around ECB-BDNF device proximity after 2-months of BDNF delivery. CONCLUSIONS: The result of this study supports the use of ECB device as a promising drug-delivery approach to locally administer BBB-impermeable factors for treating neurodegenerative conditions like AD. Optimization of the mouse-sized devices to reduce variability of BDNF release is needed to employ the ECB platform in future pre-clinical research and therapy development studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-023-01282-x. BioMed Central 2023-08-18 /pmc/articles/PMC10436657/ /pubmed/37596686 http://dx.doi.org/10.1186/s13195-023-01282-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Tambaro, Simone Mitra, Sumonto Gera, Ruchi Linderoth, Bengt Wahlberg, Lars U. Darreh-Shori, Taher Behbahani, Homira Nilsson, Per Eriksdotter, Maria Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title | Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title_full | Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title_fullStr | Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title_full_unstemmed | Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title_short | Feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of BDNF to App(NL−G−F) knock-in Alzheimer mice |
title_sort | feasibility and therapeutical potential of local intracerebral encapsulated cell biodelivery of bdnf to app(nl−g−f) knock-in alzheimer mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436657/ https://www.ncbi.nlm.nih.gov/pubmed/37596686 http://dx.doi.org/10.1186/s13195-023-01282-x |
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