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Suppression of Tau Propagation Using an Inhibitor That Targets the DK-switch of nSMase2

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

Biochem Biophys Res Commun. 2018 May 23;499(4):751-757.

PMID: 29604274

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14513156-A	Cambinol		14513-15-6	Price

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