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Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model

Alzheimer’s disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major chall...

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Autor principal: Humpel, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100061/
https://www.ncbi.nlm.nih.gov/pubmed/33967739
http://dx.doi.org/10.3389/fnagi.2021.649646
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author Humpel, Christian
author_facet Humpel, Christian
author_sort Humpel, Christian
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description Alzheimer’s disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small Aβ depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the Aβ degrading enzyme neprilysin delivered to the mouse brain can clear Aβ plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect.
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spelling pubmed-81000612021-05-07 Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model Humpel, Christian Front Aging Neurosci Neuroscience Alzheimer’s disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small Aβ depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the Aβ degrading enzyme neprilysin delivered to the mouse brain can clear Aβ plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect. Frontiers Media S.A. 2021-04-22 /pmc/articles/PMC8100061/ /pubmed/33967739 http://dx.doi.org/10.3389/fnagi.2021.649646 Text en Copyright © 2021 Humpel. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Humpel, Christian
Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title_full Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title_fullStr Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title_full_unstemmed Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title_short Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
title_sort intranasal delivery of collagen-loaded neprilysin clears beta-amyloid plaques in a transgenic alzheimer mouse model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100061/
https://www.ncbi.nlm.nih.gov/pubmed/33967739
http://dx.doi.org/10.3389/fnagi.2021.649646
work_keys_str_mv AT humpelchristian intranasaldeliveryofcollagenloadedneprilysinclearsbetaamyloidplaquesinatransgenicalzheimermousemodel