amyloid-beta-peptides and wogonin

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.

Topics: Amyloid beta-Peptides; Animals; Astrocytes; Autophagy; Cells, Cultured; Dose-Response Relationship, Drug; Embryo, Mammalian; Flavanones; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Green Fluorescent Proteins; Humans; Microscopy, Confocal; Neuroblastoma; Peptide Fragments; Phosphorylation; Signal Transduction; tau Proteins; TOR Serine-Threonine Kinases; Transfection