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Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model

Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present,...

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Autores principales: Versele, Romain, Corsi, Mariangela, Fuso, Andrea, Sevin, Emmanuel, Businaro, Rita, Gosselet, Fabien, Fenart, Laurence, Candela, Pietra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037612/
https://www.ncbi.nlm.nih.gov/pubmed/32023814
http://dx.doi.org/10.3390/ijms21030934
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author Versele, Romain
Corsi, Mariangela
Fuso, Andrea
Sevin, Emmanuel
Businaro, Rita
Gosselet, Fabien
Fenart, Laurence
Candela, Pietra
author_facet Versele, Romain
Corsi, Mariangela
Fuso, Andrea
Sevin, Emmanuel
Businaro, Rita
Gosselet, Fabien
Fenart, Laurence
Candela, Pietra
author_sort Versele, Romain
collection PubMed
description Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.
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spelling pubmed-70376122020-03-11 Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model Versele, Romain Corsi, Mariangela Fuso, Andrea Sevin, Emmanuel Businaro, Rita Gosselet, Fabien Fenart, Laurence Candela, Pietra Int J Mol Sci Article Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches. MDPI 2020-01-31 /pmc/articles/PMC7037612/ /pubmed/32023814 http://dx.doi.org/10.3390/ijms21030934 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Versele, Romain
Corsi, Mariangela
Fuso, Andrea
Sevin, Emmanuel
Businaro, Rita
Gosselet, Fabien
Fenart, Laurence
Candela, Pietra
Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title_full Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title_fullStr Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title_full_unstemmed Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title_short Ketone Bodies Promote Amyloid-β(1–40) Clearance in a Human in Vitro Blood–Brain Barrier Model
title_sort ketone bodies promote amyloid-β(1–40) clearance in a human in vitro blood–brain barrier model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037612/
https://www.ncbi.nlm.nih.gov/pubmed/32023814
http://dx.doi.org/10.3390/ijms21030934
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