SIRT3 activator Honokiol attenuates β-Amyloid by modulating amyloidogenic pathway

Honokiol (poly-phenolic lignan from Magnolia grandiflora) is a Sirtuin-3 (SIRT3) activator which exhibit antioxidant activity and augment mitochondrial functions in several experimental models. Modern evidence suggests the critical role of SIRT3 in the progression of several metabolic and neurodegenerative diseases. Amyloid beta (A beta), the precursor to extracellular senile plaques, accumulates in the brains of patients with Alzheimer's disease (AD) and is related to the development of cognitive impairment and neuronal cell death. A beta is generated from amyloid-beta precursor protein (APP) through sequential cleavages, first by beta-secretase and then by gamma-secretase. Drugs modulating this pathway are believed to be one of the most promising strategies for AD treatment. In the present study, we found that Honokiol significantly enhanced SIRT3 expression, reduced reactive oxygen species generation and lipid peroxidation, enhanced antioxidant activities, and mitochondrial function thereby reducing A beta and sAPP beta levels in Chinese Hamster Ovarian (CHO) cells (carrying the amyloid precursor protein-APP and Presenilin PS1 mutation). Mechanistic studies revealed that Honokiol affects neither protein levels of APP nor alpha-secretase activity. In contrast, Honokiol increased the expression of AMPK, CREB, and PGC-1 alpha, thereby inhibiting beta-secretase activity leading to reduced A beta levels. These results suggest that Honokiol is an activator of SIRT3 capable of improving antioxidant activity, mitochondrial energy regulation, while decreasing A beta, thereby indicating it to be a lead compound for AD drug development.