Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2
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 d...
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Published in | Biochemical and biophysical research communications Vol. 499; no. 4; pp. 751 - 757 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
23.05.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0006-291X 1090-2104 |
DOI: | 10.1016/j.bbrc.2018.03.209 |