Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content.
J Cell Mol Med
; 12(5B): 1990-2002, 2008 Oct.
Article
en En
| MEDLINE
| ID: mdl-18194465
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 Abeta42 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-beta-cyclodextrin. The resistance to amyloid toxicity and the early cytosolic Ca2+ rise following exposure to Abeta42 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 Abeta toxicity featuring seladin-1/DHCR 24 as a possible new susceptibility gene for sporadic AD.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Colesterol
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Péptidos beta-Amiloides
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Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH
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Membranas
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Proteínas del Tejido Nervioso
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Neuroblastoma
Límite:
Humans
Idioma:
En
Revista:
J Cell Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2008
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Reino Unido