Cargando…

Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology

The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer’s disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the br...

Descripción completa

Detalles Bibliográficos
Autores principales: Lazar, Adina-Nicoleta, Hanbouch, Linda, Boussicaut, Lydie, Fourmaux, Baptiste, Daira, Patricia, Millan, Mark J., Bernoud-Hubac, Nathalie, Potier, Marie-Claude
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688773/
https://www.ncbi.nlm.nih.gov/pubmed/36429044
http://dx.doi.org/10.3390/cells11223616
_version_ 1784836354027290624
author Lazar, Adina-Nicoleta
Hanbouch, Linda
Boussicaut, Lydie
Fourmaux, Baptiste
Daira, Patricia
Millan, Mark J.
Bernoud-Hubac, Nathalie
Potier, Marie-Claude
author_facet Lazar, Adina-Nicoleta
Hanbouch, Linda
Boussicaut, Lydie
Fourmaux, Baptiste
Daira, Patricia
Millan, Mark J.
Bernoud-Hubac, Nathalie
Potier, Marie-Claude
author_sort Lazar, Adina-Nicoleta
collection PubMed
description The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer’s disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.
format Online
Article
Text
id pubmed-9688773
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96887732022-11-25 Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology Lazar, Adina-Nicoleta Hanbouch, Linda Boussicaut, Lydie Fourmaux, Baptiste Daira, Patricia Millan, Mark J. Bernoud-Hubac, Nathalie Potier, Marie-Claude Cells Article The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer’s disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention. MDPI 2022-11-15 /pmc/articles/PMC9688773/ /pubmed/36429044 http://dx.doi.org/10.3390/cells11223616 Text en © 2022 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
Lazar, Adina-Nicoleta
Hanbouch, Linda
Boussicaut, Lydie
Fourmaux, Baptiste
Daira, Patricia
Millan, Mark J.
Bernoud-Hubac, Nathalie
Potier, Marie-Claude
Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title_full Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title_fullStr Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title_full_unstemmed Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title_short Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology
title_sort lipid dys-homeostasis contributes to apoe4-associated ad pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688773/
https://www.ncbi.nlm.nih.gov/pubmed/36429044
http://dx.doi.org/10.3390/cells11223616
work_keys_str_mv AT lazaradinanicoleta lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT hanbouchlinda lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT boussicautlydie lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT fourmauxbaptiste lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT dairapatricia lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT millanmarkj lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT bernoudhubacnathalie lipiddyshomeostasiscontributestoapoe4associatedadpathology
AT potiermarieclaude lipiddyshomeostasiscontributestoapoe4associatedadpathology