Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme

The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate...

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Autores principales:	Janine Mett, Anna A. Lauer, Daniel Janitschke, Lea V. Griebsch, Elena L. Theiss, Heike S. Grimm, Hennariikka Koivisto, Heikki Tanila, Tobias Hartmann, Marcus O. W. Grimm
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Aβ degradation insulin-degrading enzyme Alzheimer´s disease fatty acids medium-chain fatty acids lauric acid Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/51f0d0b2950043ddab3e86c9b4bb0715
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spelling	oai:doaj.org-article:51f0d0b2950043ddab3e86c9b4bb07152021-11-25T17:09:26ZMedium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme10.3390/cells101129412073-4409https://doaj.org/article/51f0d0b2950043ddab3e86c9b4bb07152021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2941https://doaj.org/toc/2073-4409The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease.Janine MettAnna A. LauerDaniel JanitschkeLea V. GriebschElena L. TheissHeike S. GrimmHennariikka KoivistoHeikki TanilaTobias HartmannMarcus O. W. GrimmMDPI AGarticleAβ degradationinsulin-degrading enzymeAlzheimer´s diseasefatty acidsmedium-chain fatty acidslauric acidBiology (General)QH301-705.5ENCells, Vol 10, Iss 2941, p 2941 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aβ degradation insulin-degrading enzyme Alzheimer´s disease fatty acids medium-chain fatty acids lauric acid Biology (General) QH301-705.5
spellingShingle	Aβ degradation insulin-degrading enzyme Alzheimer´s disease fatty acids medium-chain fatty acids lauric acid Biology (General) QH301-705.5 Janine Mett Anna A. Lauer Daniel Janitschke Lea V. Griebsch Elena L. Theiss Heike S. Grimm Hennariikka Koivisto Heikki Tanila Tobias Hartmann Marcus O. W. Grimm Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
description	The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease.
format	article
author	Janine Mett Anna A. Lauer Daniel Janitschke Lea V. Griebsch Elena L. Theiss Heike S. Grimm Hennariikka Koivisto Heikki Tanila Tobias Hartmann Marcus O. W. Grimm
author_facet	Janine Mett Anna A. Lauer Daniel Janitschke Lea V. Griebsch Elena L. Theiss Heike S. Grimm Hennariikka Koivisto Heikki Tanila Tobias Hartmann Marcus O. W. Grimm
author_sort	Janine Mett
title	Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
title_short	Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
title_full	Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
title_fullStr	Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
title_full_unstemmed	Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
title_sort	medium-chain length fatty acids enhance aβ degradation by affecting insulin-degrading enzyme
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/51f0d0b2950043ddab3e86c9b4bb0715
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Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme

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