These authors equally contributed to this work.
Seladin-1/DHCR24 protects neuroblastoma cells against Aβ toxicity by increasing membrane cholesterol content
Version of Record online: 11 JAN 2008
© 2007 The Authors Journal compilation © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Journal of Cellular and Molecular Medicine
Volume 12, Issue 5b, pages 1990–2002, October 2008
How to Cite
Cecchi, C., Rosati, F., Pensalfini, A., Formigli, L., Nosi, D., Liguri, G., Dichiara, F., Morello, M., Danza, G., Pieraccini, G., Peri, A., Serio, M. and Stefani, M. (2008), Seladin-1/DHCR24 protects neuroblastoma cells against Aβ toxicity by increasing membrane cholesterol content. Journal of Cellular and Molecular Medicine, 12: 1990–2002. doi: 10.1111/j.1582-4934.2008.00216.x
- Issue online: 30 OCT 2008
- Version of Record online: 11 JAN 2008
- Received: July 2, 2007; Accepted: December 28, 2007
- Aβ peptides;
- Alzheimer's disease;
- amyloid toxicity;
- membrane cholesterol;
The role of brain cholesterol in Alzheimer's disease (AD) is currently a matter of debate. Experimental evidence suggests that reducing circulating and brain cholesterol protects against AD, however recent data indicate that low membrane cholesterol results in neurode-generation and that the cholesterol synthesis catalyst seladin-1 is down-regulated in AD-affected brain regions. We previously reported a significant correlation between resistance to amyloid toxicity and content of membrane cholesterol in differing cultured cell types. Here we provide evidence that Aβ42 pre-fibrillar aggregates accumulate more slowly and in reduced amount at the plasma membrane of human SH-SY5Y neuroblastoma cells overexpressing seladin-1 or treated with PEG-cholesterol than at the membrane of control cells. The accumulation was significantly increased in cholesterol-depleted cells following treatment with the specific seladin-1 inhibitor 5,22E-cholestadien-3-ol or with methyl-β-cyclodextrin. The resistance to amyloid toxicity and the early cytosolic Ca2+ rise following exposure to Aβ42 aggregates were increased and prevented, respectively, by increasing membrane cholesterol whereas the opposite effects were found in cholesterol-depleted cells. These results suggest that seladin-1-dependent cholesterol synthesis reduces membrane-aggregate interaction and cell damage associated to amyloid-induced imbalance of cytosolic Ca2+. Our findings extend recently reported data indicating that seladin-1 overexpression directly enhances the resistance to Aβ toxicity featuring seladin-1/DHCR 24 as a possible new susceptibility gene for sporadic AD.