Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2

Biochem Biophys Res Commun. 2018 May 23;499(4):751-757. doi: 10.1016/j.bbrc.2018.03.209. Epub 2018 Apr 9.


Targeting of molecular pathways involved in the cell-to-cell propagation of pathological tau species is a novel approach for development of disease-modifying therapies that could block tau pathology and attenuate cognitive decline in patients with Alzheimer's disease and other tauopathies. We discovered cambinol through a screening effort and show that it is an inhibitor of cell-to-cell tau propagation. Our in vitro data demonstrate that cambinol inhibits neutral sphingomyelinase 2 (nSMase2) enzyme activity in dose response fashion, and suppresses extracellular vesicle (EV) production while reducing tau seed propagation. Our in vivo testing with cambinol shows that it can reduce the nSMase2 activity in the brain after oral administration. Our molecular docking and simulation analysis reveals that cambinol can target the DK-switch in the nSMase2 active site.

Keywords: Cambinol; Extracellular vesicles; Molecular modeling; Tau biosensor; Tauopathy; nSMase2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosensing Techniques
  • Brain / metabolism
  • Cell-Free System
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Vesicles / metabolism
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Models, Molecular
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Permeability
  • Protein Domains
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / chemistry*
  • Sphingomyelin Phosphodiesterase / metabolism
  • Tissue Extracts
  • tau Proteins / antagonists & inhibitors
  • tau Proteins / metabolism*


  • Enzyme Inhibitors
  • Naphthalenes
  • Pyrimidinones
  • Tissue Extracts
  • cambinol
  • tau Proteins
  • SMPD3 protein, human
  • Smpd3 protein, mouse
  • Sphingomyelin Phosphodiesterase