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

• Published in: Biochemical and biophysical research communications Vol. 499; no. 4; pp. 751 - 757
• Main Authors: Bilousova, Tina, Elias, Chris, Miyoshi, Emily, Alam, Mohammad Parvez, Zhu, Chunni, Campagna, Jesus, Vadivel, Kanagasabai, Jagodzinska, Barbara, Gylys, Karen Hoppens, John, Varghese
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2018
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Biosensing Techniques; BRAIN; Brain - metabolism; Cambinol; Cell-Free System; ENZYME ACTIVITY; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Extracellular vesicles; Extracellular Vesicles - metabolism; HEK293 Cells; Humans; Mice, Inbred C57BL; Models, Molecular; Molecular modeling; Naphthalenes - chemistry; Naphthalenes - pharmacology; nSMase2; ORAL ADMINISTRATION; Permeability; Protein Domains; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - chemistry; Sphingomyelin Phosphodiesterase - metabolism; Tau biosensor; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism; Tauopathy; THERAPY; Tissue Extracts; Extracellular vesicles; Tau biosensor; Cambinol; Tauopathy; nSMase2; Molecular modeling
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.03.209

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. [Display omitted] •Cambinol inhibits spread of AD synaptosome derived tau seeds, from donor to recipient cells.•Cambinol inhibits nSMase2 through targeting the DK-switch in its active site.•Cambinol inhibits EV-mediated tau propagation.•Cambinol has low brain permeability and inhibition of nSMase activity in vivo.