Piceatannol, a natural analogue of resveratrol, effectively reduces beta-amyloid levels via activation of alpha-secretase and matrix metalloproteinase-9

• Resveratrol, oxyresveratrol, and piceatannol induce apoptosis and autophagy at higher doses.
• Resveratrol, oxyresveratrol, and piceatannol decrease γ-secretase processing at higher doses.
• Piceatannol increases α-secretase processing and activates MMP-9 at lower doses.
• Piceatannol is the only resveratrol analogue that reduces Aβ levels without cytotoxicity.

Beta-amyloid (Aβ) is a major pathogenic molecule in Alzheimer's disease (AD). The mechanisms of Aβ reduction by resveratrol and its analogues, oxyresveratrol and piceatannol were investigated through examination of amyloid precursor protein (APP) processing and Aβ degradation enzyme activities. In Neuro2a cells, all compounds induced caspase-3-dependent cell death and autophagy, and reduced γ-secretase activity at higher doses. Piceatannol significantly increased α-secretase activity at lower doses. In addition, resveratrol induced MMP-9 activation at higher dose and piceatannol activated MMP-9 at lower doses and cathepsin B at higher doses. In APPsw expressing HEK293 cells, resveratrol and oxyresveratrol only reduced Aβ at higher concentrations, but piceatannol showed significant Aβ reduction regardless of its concentration or cell viability. Taken together, piceatannol had the greatest ability compared to resveratrol and oxyresveratrol to lower Aβ levels without causing cell death, and the mechanisms behind this effect involve the activation of α-secretase and MMP-9.