Glaucocalyxin A as a natural product increases amyloid β clearance and decreases tau phosphorylation involving the mammalian target of rapamycin signaling pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder correlated with age, characterized by the accumulation of amyloid beta (A beta) plaques and neurofibrillary tangles. The mammalian target of rapamycin (mTOR) is an important protein that regulates A beta clearance and tau phosphorylation. Therefore, mTOR has become a pivotal therapeutic target for AD treatment. In this study, we discovered a natural product, glaucocalyxin A (GLA), as a new mTOR inhibitor based on a high-throughput screening platform with alpha-screen technology against our natural product library. Further study showed that GLA increased A beta clearance involving the protein kinase B/mTOR/autophagy signaling pathway and inhibited tau phosphorylation involving the mTOR/70-kDa ribosomal protein S6 kinase pathway, which highlighted the therapeutic potential of GLA for the AD treatment.