title: Glimepiride attenuates Aβ production via suppressing BACE1 activity in cortical neurons.
abstract: Numerous lines of evidence suggest a strong link between diabetes mellitus and Alzheimer's disease (AD). Impaired insulin signaling and insulin resistance occur not only in diabetes but also in the brain of AD. Recent evidence has indicated that peroxisome proliferator-activated receptor γ (PPARγ) agonists thiazolidinediones (TZDs) can decrease β-amyloid peptide (Aβ) deposition, which is the core component of senile plaques in AD, but the underlying mechanisms still remain unclear. In this study, we investigated whether glimepiride with PPARγ-stimulating activity, an oral anti-diabetic drug, has similar effects on Aβ production in primary cortical neurons. We demonstrated that glimepiride decreased extracellular Aβ40 and Aβ42 levels. The effect of glimepiride on reduction of Aβ40 generation was mediated by downregulation of β-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression, and by suppression of BACE1 activity. In addition, we found that high glucose condition enhanced Aβ40 production and glimepiride significantly decreased high glucose-induced Aβ40 production. Finally, a specific PPARγ antagonist GW9662 reversed glimepiride inhibitory effect on Aβ40 generation, suggesting a PPARγ-dependent mechanism may be involved. Our data indicated that glimepiride may serve as a promising drug for the treatment of AD associated with diabetes.
authors.affiliation: Neurobiology Lab, National Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; AD; Alzheimer's disease; Aβ; BACE1; DM; DMSO; ELISA; GAPDH; GLP-1; Glimepiride; MTT; PPARγ; PPARγ agonist; RT-PCR; TZDs; diabetes mellitus; dimethyl sulfoxide; enzyme-linked immunosorbent assay; glucagon-like peptide-1; glyceraldehyde-3-phosphatedehydrogenase; peroxisome proliferator-activated receptor γ; real-time polymerase chain reaction; thiazolidinediones; β-Amyloid; β-amyloid peptide; β-site APP-cleaving enzyme 1