Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model

With age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer’s disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in th...

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Autores principales: Huguenard, Claire J. C., Cseresznye, Adam, Darcey, Teresa, Nkiliza, Aurore, Evans, James E., Hazen, Stanley L., Mullan, Michael, Crawford, Fiona, Abdullah, Laila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853982/
https://www.ncbi.nlm.nih.gov/pubmed/36688151
http://dx.doi.org/10.3389/fnagi.2022.1059017
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author Huguenard, Claire J. C.
Cseresznye, Adam
Darcey, Teresa
Nkiliza, Aurore
Evans, James E.
Hazen, Stanley L.
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
author_facet Huguenard, Claire J. C.
Cseresznye, Adam
Darcey, Teresa
Nkiliza, Aurore
Evans, James E.
Hazen, Stanley L.
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
author_sort Huguenard, Claire J. C.
collection PubMed
description With age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer’s disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human APOE (APOE-TR). Aged APOE-TR mice were also orally administered 125 mg/kg of L-carnitine daily for 7 days followed by evaluation of brain, liver, and plasma L-carnitine system metabolites. Compared to E4-TR, an age-dependent increase among E2- and E3-TR mice was detected for medium- and long-chain acylcarnitines (MCA and LCA, respectively) within the cerebrovasculature and brain parenchyma. While following L-carnitine oral challenge, E4-TR mice had higher increases in the L-carnitine metabolites, GBB and crotonobetaine in the brain and a reduction of plasma to brain total acylcarnitine ratios compared to other genotypes. These studies suggest that with aging, the presence of the E4 allele may contribute to alterations in the L-carnitine bioenergetic system and to the generation of L-carnitine metabolites that could have detrimental effects on the vascular system. Collectively the E4 allele and aging may therefore contribute to AD pathogenesis through aging-related lipid bioenergetics as well as cerebrovascular dysfunctions.
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spelling pubmed-98539822023-01-21 Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model Huguenard, Claire J. C. Cseresznye, Adam Darcey, Teresa Nkiliza, Aurore Evans, James E. Hazen, Stanley L. Mullan, Michael Crawford, Fiona Abdullah, Laila Front Aging Neurosci Aging Neuroscience With age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer’s disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human APOE (APOE-TR). Aged APOE-TR mice were also orally administered 125 mg/kg of L-carnitine daily for 7 days followed by evaluation of brain, liver, and plasma L-carnitine system metabolites. Compared to E4-TR, an age-dependent increase among E2- and E3-TR mice was detected for medium- and long-chain acylcarnitines (MCA and LCA, respectively) within the cerebrovasculature and brain parenchyma. While following L-carnitine oral challenge, E4-TR mice had higher increases in the L-carnitine metabolites, GBB and crotonobetaine in the brain and a reduction of plasma to brain total acylcarnitine ratios compared to other genotypes. These studies suggest that with aging, the presence of the E4 allele may contribute to alterations in the L-carnitine bioenergetic system and to the generation of L-carnitine metabolites that could have detrimental effects on the vascular system. Collectively the E4 allele and aging may therefore contribute to AD pathogenesis through aging-related lipid bioenergetics as well as cerebrovascular dysfunctions. Frontiers Media S.A. 2023-01-06 /pmc/articles/PMC9853982/ /pubmed/36688151 http://dx.doi.org/10.3389/fnagi.2022.1059017 Text en Copyright © 2023 Huguenard, Cseresznye, Darcey, Nkiliza, Evans, Hazen, Mullan, Crawford and Abdullah. 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 Aging Neuroscience
Huguenard, Claire J. C.
Cseresznye, Adam
Darcey, Teresa
Nkiliza, Aurore
Evans, James E.
Hazen, Stanley L.
Mullan, Michael
Crawford, Fiona
Abdullah, Laila
Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title_full Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title_fullStr Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title_full_unstemmed Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title_short Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model
title_sort age and apoe affect l-carnitine system metabolites in the brain in the apoe-tr model
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853982/
https://www.ncbi.nlm.nih.gov/pubmed/36688151
http://dx.doi.org/10.3389/fnagi.2022.1059017
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