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

Tina Bilousova; Chris Elias; Emily Miyoshi; Mohammad Parvez Alam; Chunni Zhu; Jesus Campagna; Kanagasabai Vadivel; Barbara Jagodzinska; Karen Hoppens Gylys; Varghese John

doi:10.1016/j.bbrc.2018.03.209

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.

Affiliations

¹ Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA; Gylys Lab, School of Nursing, University of California, Los Angeles, CA, USA.
² Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA.
³ Gylys Lab, School of Nursing, University of California, Los Angeles, CA, USA.
⁴ Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, USA. Electronic address: vjohn@mednet.ucla.edu.

Abstract

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*

Substances

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

Grants and funding

R01 AG051386/AG/NIA NIH HHS/United States