title: Wogonin increases β-amyloid clearance and inhibits tau phosphorylation via inhibition of mammalian target of rapamycin: potential drug to treat Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Many molecular lesions have been detected in AD, of which the most commonly observed is the accumulation of misfolded proteins, including β-amyloid (Aβ40 and Aβ42) and tau, in the aging brain. The mammalian target of rapamycin (mTOR) pathway mediates Aβ clearance through autophagy and regulates tau phosphorylation via glycogen synthase kinase-3β (GSK3β). Thus, mTOR becomes an important therapeutic target for AD. However, no mTOR inhibitor has yet been marketed to treat AD. Here, we discovered a natural product, wogonin, which could potently promote Aβ clearance in the primary neural astrocytes and significantly decrease Aβ secretion in SH-SY5Y-APP and BACE1 cells [SH-SY5Y cells stably expressing the human amyloid precursor protein (APP) and β-secretase (BACE1)] through the mTOR/autophagy signaling pathway. Additionally, further research revealed that wogonin inhibited the activity of GSK3β via mTOR inhibition, finally leading to tau phosphorylation reduction in SH-SHY5Y cells and primary neural astrocytes. In conclusion, our study identified a small molecule, wogonin, which could effectively promote Aβ clearance and decrease tau phosphorylation, and highlighted its therapeutic potential for AD treatment.
authors.affiliation: Department of Neurology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230001, China, horror2001@sina.com.
authors.forename: Yuyou
authors.initials: Y
authors.lastname: Zhu
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D044950:Flavanones / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D044950:Flavanones; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D049452:Green Fluorescent Proteins; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C085514:wogonin