U18666A-mediated apoptosis in cultured murine cortical neurons : role of caspases, calpains and kinases

Koh, Chor Hui Vivien, Qi, Robert Z., Qu, Dianbo, Melendez, Alirio, Manikandan, Jayapal, Bay, Boon Huat, Duan, Wei and Cheung, Nam Sang 2006, U18666A-mediated apoptosis in cultured murine cortical neurons : role of caspases, calpains and kinases, Cellular signalling, vol. 18, no. 10, pp. 1572-1583.

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Title U18666A-mediated apoptosis in cultured murine cortical neurons : role of caspases, calpains and kinases
Author(s) Koh, Chor Hui Vivien
Qi, Robert Z.
Qu, Dianbo
Melendez, Alirio
Manikandan, Jayapal
Bay, Boon Huat
Duan, Wei
Cheung, Nam Sang
Journal name Cellular signalling
Volume number 18
Issue number 10
Start page 1572
End page 1583
Publisher Elsvier Inc.
Place of publication Amsterdam, Netherlands
Publication date 2006-10
ISSN 0898-6568
1873-3913
Keyword(s) U18666A
Caspase
Calpain
Tau
Kinase
neuronal apoptosis
Summary Studies have suggested that cholesterol imbalance in the brain might be related to the development of neurological disorders such as Alzheimer's disease and Niemann–Pick disease type C. Previously, we have reported that U18666A, a cholesterol transport-inhibiting agent, leads to apoptosis and intracellular cholesterol accumulation in primary cortical neurons. In this study, we examined the effects of U18666A-mediated neuronal apoptosis, and found that chronic exposure to U18666A led to the activation of caspases and calpains and hyperphosphorylation of tau. Tau hyperphosphorylation is regulated by several kinases that phosphorylate specific sites of tau in vitro. Surprisingly, the kinase activity of cyclin-dependent kinase 5 decreased in U18666A-treated cortical neurons whereas its protein level remained unchanged. The amount of glycogen synthase kinase 3 and mitogen-activated protein kinases were found to decrease in their phosphorylated states by Western blot analysis. Gene transcription was further studied using microarray analysis. Genes encoding for kinases and phosphatases were differentially expressed with most up-regulated and some down-regulated in expression upon U18666A treatment. The activation of cysteine proteases and cholesterol accumulation with tauopathies may provide clues to the cellular mechanism of the inhibition of cholesterol transport-mediated cell death in neurodegenerative diseases.
Language eng
Field of Research 110902 Cellular Nervous System
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2005, Elsevier Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009171

Document type: Journal Article
Collection: School of Medicine
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