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Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport

Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (...

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Autores principales: Nguyen, Steven, Banks, William A., Rhea, Elizabeth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395935/
https://www.ncbi.nlm.nih.gov/pubmed/34449653
http://dx.doi.org/10.3390/medsci9030056
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author Nguyen, Steven
Banks, William A.
Rhea, Elizabeth M.
author_facet Nguyen, Steven
Banks, William A.
Rhea, Elizabeth M.
author_sort Nguyen, Steven
collection PubMed
description Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (CNS) insulin must first cross the blood–brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling.
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spelling pubmed-83959352021-08-28 Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport Nguyen, Steven Banks, William A. Rhea, Elizabeth M. Med Sci (Basel) Article Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (CNS) insulin must first cross the blood–brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling. MDPI 2021-08-25 /pmc/articles/PMC8395935/ /pubmed/34449653 http://dx.doi.org/10.3390/medsci9030056 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nguyen, Steven
Banks, William A.
Rhea, Elizabeth M.
Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title_full Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title_fullStr Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title_full_unstemmed Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title_short Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport
title_sort effects of rapamycin on insulin brain endothelial cell binding and blood–brain barrier transport
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395935/
https://www.ncbi.nlm.nih.gov/pubmed/34449653
http://dx.doi.org/10.3390/medsci9030056
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