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The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex
- Source :
- PLoS ONE, Vol 9, Iss 7, p e102420 (2014), PLOS ONE 9(7), e102420 (2014). doi:10.1371/journal.pone.0102420, PLoS ONE
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
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.
- Subjects :
- medicine.medical_treatment
metabolism [Microtubule Proteins]
genetics [Amyloid Precursor Protein Secretases]
Pharmacology
Mice
Cell Signaling
drug therapy [Alzheimer Disease]
Aspartic Acid Endopeptidases
metabolism [Transcription Factors]
Senile plaques
Phosphorylation
Multidisciplinary
biology
Nuclear Proteins
metabolism [Aspartic Acid Endopeptidases]
Metformin
Ubiquitin ligase
metabolism [Ribosomal Protein S6 Kinases]
Microtubule Proteins
Medicine
Female
Alzheimer's disease
metabolism [Nuclear Proteins]
medicine.drug
Research Article
Signal Transduction
medicine.medical_specialty
Ubiquitin-Protein Ligases
Science
Tau protein
pharmacology [Hypoglycemic Agents]
Alzheimer Disease
Internal medicine
Diabetes mellitus
Cell Line, Tumor
BACE1 protein, human
mental disorders
medicine
Animals
Humans
Hypoglycemic Agents
ddc:610
Insulin
Ribosomal Protein S6 Kinases
Biology and Life Sciences
Cell Biology
medicine.disease
metabolism [Amyloid Precursor Protein Secretases]
Mice, Inbred C57BL
Endocrinology
genetics [Aspartic Acid Endopeptidases]
Cellular Neuroscience
Protein Biosynthesis
Proteolysis
biology.protein
pharmacology [Metformin]
Molecular Neuroscience
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
Protein Processing, Post-Translational
Neuroscience
Transcription Factors
Mid1 protein, human
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....4771a072d5c69d70888a4a45114c9d4b