SIRT3 activator Honokiol attenuates β-Amyloid by modulating amyloidogenic pathway

PLoS One. 2018 Jan 11;13(1):e0190350. doi: 10.1371/journal.pone.0190350. eCollection 2018.

Abstract

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 (Aβ), 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. Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages, first by β-secretase and then by γ-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 Aβ and sAPPβ 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 α-secretase activity. In contrast, Honokiol increased the expression of AMPK, CREB, and PGC-1α, thereby inhibiting β-secretase activity leading to reduced Aβ levels. These results suggest that Honokiol is an activator of SIRT3 capable of improving antioxidant activity, mitochondrial energy regulation, while decreasing Aβ, thereby indicating it to be a lead compound for AD drug development.

MeSH terms

  • Adenylate Kinase / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Biphenyl Compounds / pharmacology*
  • CHO Cells
  • Cricetulus
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Humans
  • Lignans / pharmacology*
  • Lipid Peroxidation / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism
  • Sirtuin 3 / drug effects*

Substances

  • Amyloid beta-Peptides
  • Biphenyl Compounds
  • Cyclic AMP Response Element-Binding Protein
  • Lignans
  • Reactive Oxygen Species
  • honokiol
  • Adenylate Kinase
  • SIRT3 protein, human
  • Sirtuin 3

Grant support

The authors received no specific funding for this work.