The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.

Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregula...

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Autores principales:	Moritz M Hettich, Frank Matthes, Devon P Ryan, Nadine Griesche, Susanne Schröder, Stephanie Dorn, Sybille Krauβ, Dan Ehninger
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/42649d0e94c24c4ca876da763496d3f4
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spelling	oai:doaj.org-article:42649d0e94c24c4ca876da763496d3f42021-11-25T06:08:25ZThe anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.1932-620310.1371/journal.pone.0102420https://doaj.org/article/42649d0e94c24c4ca876da763496d3f42014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25025689/?tool=EBIhttps://doaj.org/toc/1932-6203Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.Moritz M HettichFrank MatthesDevon P RyanNadine GriescheSusanne SchröderStephanie DornSybille KrauβDan EhningerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e102420 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Moritz M Hettich Frank Matthes Devon P Ryan Nadine Griesche Susanne Schröder Stephanie Dorn Sybille Krauβ Dan Ehninger The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
description	Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.
format	article
author	Moritz M Hettich Frank Matthes Devon P Ryan Nadine Griesche Susanne Schröder Stephanie Dorn Sybille Krauβ Dan Ehninger
author_facet	Moritz M Hettich Frank Matthes Devon P Ryan Nadine Griesche Susanne Schröder Stephanie Dorn Sybille Krauβ Dan Ehninger
author_sort	Moritz M Hettich
title	The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
title_short	The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
title_full	The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
title_fullStr	The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
title_full_unstemmed	The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
title_sort	anti-diabetic drug metformin reduces bace1 protein level by interfering with the mid1 complex.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/42649d0e94c24c4ca876da763496d3f4
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The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.

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