Journal Article

DZNE-2020-03811

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.

Hettich, M. M. (First author)DZNE* ; Matthes, F.DZNE* ; Ryan, D. P.DZNE* ; Griesche, N.DZNE* ; Schröder, S.DZNE* ; Dorn, S.DZNE* ; Krauß, S.DZNE* ; Ehninger, D. (Last author)DZNE*

2014
PLOS San Francisco, California, US

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Please use a persistent id in citations: doi:10.1371/journal.pone.0102420

Abstract: 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.

Keyword(s): Ubiquitin-Protein Ligases (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Amyloid Precursor Protein Secretases: genetics (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: genetics (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Hypoglycemic Agents: pharmacology (MeSH) ; Metformin: pharmacology (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Microtubule Proteins: metabolism (MeSH) ; Nuclear Proteins: metabolism (MeSH) ; Phosphorylation (MeSH) ; Protein Biosynthesis (MeSH) ; Protein Processing, Post-Translational (MeSH) ; Proteolysis (MeSH) ; Ribosomal Protein S6 Kinases: metabolism (MeSH) ; Transcription Factors: metabolism (MeSH) ; Hypoglycemic Agents ; Microtubule Proteins ; Nuclear Proteins ; Transcription Factors ; Metformin ; Mid1 protein, human ; Ribosomal Protein S6 Kinases ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; BACE1 protein, human

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Contributing Institute(s):

1. Molecular and Cellular Cognition (AG Ehninger)
2. Animal Facility Bonn (Animal Facility Bonn)
3. Regulatory RNA-protein interaction in neurodegenerative diseases (AG Krauß)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2014

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Database coverage:
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