Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

Biomolecules. 2021 Mar 13;11(3):423. doi: 10.3390/biom11030423.

Abstract

The pathological role of vitamin K2 in Alzheimer's disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-β (Aβ) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (β-CTF/APP), transfected in astroglioma C6 cells and used this cell model (β-CTF/C6) to study the protective effect of vitamin K2 against Aβ cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aβ-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aβ peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aβ-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aβ-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aβ toxicity.

Keywords: Alzheimer’s disease; Aβ cytotoxicity; PI3K/Akt/Bad; apoptosis; caspase-3; vitamin K2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Cytoprotection* / drug effects
  • Free Radicals / metabolism
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Models, Biological
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects
  • Vitamin K 2 / pharmacology*
  • Warfarin / pharmacology
  • bcl-Associated Death Protein / metabolism

Substances

  • Amyloid beta-Peptides
  • Free Radicals
  • Intercellular Signaling Peptides and Proteins
  • bcl-Associated Death Protein
  • growth arrest-specific protein 6
  • Vitamin K 2
  • Warfarin
  • Axl protein, rat
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspase 3