Seladin-1/DHCR24 protects neuroblastoma cells against Abeta toxicity by increasing membrane cholesterol content.
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.
Cecchi
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C
Department of Biochemical Sciences, University of Florence, Florence, Italy. cristina.cecchi@unifi.it
Rosati
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Pensalfini
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Formigli
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Nosi
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Liguri
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Dichiara
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Morello
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Danza
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Pieraccini
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Peri
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Serio
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Stefani
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D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D022082:Cellular Structures / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D006801:Humans; D008566:Membranes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human