ApoE4 attenuates autophagy via FoxO3a repression in the brain

Abstract Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 al...

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Autores principales:	Hee-Young Sohn, Seong-Ik Kim, Jee-Yun Park, Sung-Hye Park, Young Ho Koh, Joon Kim, Chulman Jo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1fe86be3dec44f429f36cd5c43667ceb
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spelling	oai:doaj.org-article:1fe86be3dec44f429f36cd5c43667ceb2021-12-02T19:09:31ZApoE4 attenuates autophagy via FoxO3a repression in the brain10.1038/s41598-021-97117-62045-2322https://doaj.org/article/1fe86be3dec44f429f36cd5c43667ceb2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97117-6https://doaj.org/toc/2045-2322Abstract Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.Hee-Young SohnSeong-Ik KimJee-Yun ParkSung-Hye ParkYoung Ho KohJoon KimChulman JoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hee-Young Sohn Seong-Ik Kim Jee-Yun Park Sung-Hye Park Young Ho Koh Joon Kim Chulman Jo ApoE4 attenuates autophagy via FoxO3a repression in the brain
description	Abstract Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer’s disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.
format	article
author	Hee-Young Sohn Seong-Ik Kim Jee-Yun Park Sung-Hye Park Young Ho Koh Joon Kim Chulman Jo
author_facet	Hee-Young Sohn Seong-Ik Kim Jee-Yun Park Sung-Hye Park Young Ho Koh Joon Kim Chulman Jo
author_sort	Hee-Young Sohn
title	ApoE4 attenuates autophagy via FoxO3a repression in the brain
title_short	ApoE4 attenuates autophagy via FoxO3a repression in the brain
title_full	ApoE4 attenuates autophagy via FoxO3a repression in the brain
title_fullStr	ApoE4 attenuates autophagy via FoxO3a repression in the brain
title_full_unstemmed	ApoE4 attenuates autophagy via FoxO3a repression in the brain
title_sort	apoe4 attenuates autophagy via foxo3a repression in the brain
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1fe86be3dec44f429f36cd5c43667ceb
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ApoE4 attenuates autophagy via FoxO3a repression in the brain

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