title: The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.
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.
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Moritz M
authors.initials: MM
authors.lastname: Hettich
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Matthes
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Devon P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Griesche
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schröder
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dorn
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Krauβ
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Ehninger
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008868:Microtubule Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D007004:Hypoglycemic Agents; D008868:Microtubule Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D008687:Metformin; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases; D019893:Ribosomal Protein S6 Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human