Antioxidant Compound, Oxyresveratrol, Inhibits APP Production through the AMPK/ULK1/mTORMediated Autophagy Pathway in Mouse Cortical Astrocytes
- Antioxidant Compound, Oxyresveratrol, Inhibits APP Production through the AMPK/ULK1/mTORMediated Autophagy Pathway in Mouse Cortical Astrocytes
- 남길수; 임혜원; 조윤정; Md. Ataur Rahman
- Issue Date
- VOL 10, NO 3, 408
- Oxyresveratrol (OxyR), a wellknown polyphenolic phytoalexin, possesses a wide range of pharmacological and biological properties, comprising antioxidant, antiinflammatory, free radical scavenging, anticancer, and neuroprotective activities. Autophagy is a cellular selfdegradation system that removes aggregated or misfolded intracellular components via the autophagosomelysosomal pathway. Astrocyte accumulation is one of the earliest neuropathological changes in Alzheimer’s disease (AD), and amyloid precursor protein (APP) is the hallmark of AD. OxyR could affect APP modulation via the autophagy pathway. Here, we have reported that OxyR promotes autophagy signaling and attenuates APP production in primary cortical astrocytes based on immunofluorescence and immunoblotting assay results. Cotreatment with the latestage autophagy inhibitor chloroquine (CQ) and OxyR caused significantly higher microtubuleassociated protein light chain 3 (LC3)II protein levels and LC3 puncta counts, demonstrating that OxyR stimulated autophagic flux. We also found that OxyR significantly reduced the levels of the autophagy substrate p62/SQSTM1, and p62 levels were significantly augmented by cotreatment with OxyR and CQ, because of the impaired deficiency of p62 in autolysosome. Likewise, pretreatment with the autoph agy inhibitor, 3methyladenine (3MA), resulted in significantly fewer OxyRinduced LC3 puncta and lower LC3II expression, suggesting that OxyRmediated autophagy was dependent on the class III PI3kinase pathway. In contrast, OxyR caused significantly lower LC3II protein expression when pretreated with compound C, an AMPactivated protein kinase (AMPK) inhibitor, indicating that AMPK signaling regulated the OxyRinduced autophagic pathway. Additionally, cotreatment with OxyR with rapamycin intended to inhibit the mammalian target of rapamycin (mTOR) caused significantly l
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