Seladin‐1/DHCR24 protects neuroblastoma cells against Aβ toxicity by increasing membrane cholesterol content

Article · January 2008with32 Reads
DOI: 10.1111/j.1582-4934.2008.00216.x
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.
  • ... These data suggest that yet undefined neuroprotective mechanism(s) may underlie the improved neuronal survival induced by the overexpression of DHCR24 in the used in vitro and in vivo models. Prior studies have linked the neuroprotective effects of DHCR24 directly to its cholesterol-synthesizing activity, showing cholesterol-dependent protection from oxidative stress [11] or Aβ toxicity [9] and maintenance of lipid raft integrity [10]. Here, a moderate, but statistically non-significant increase in total cellular cholesterol levels was detected, and this coincided with enhanced neuronal survival in the DHCR24-overexpressing neuron-BV2 co-cultures after the induction of neuroinflammation. ...
  • ... regions such as the inferior temporal cortex [52, 53], and the enzyme has been shown to protect neurons from Abmediated toxicity and to decrease Ab 42 production by counteracting the b-secretase cleavage of AbPP [54, 55]. Moreover, DHCR24-dependent cholesterol synthesis reduces the membrane aggregate interaction and cell damage associated with amyloid treatment [56]. Thus, our results of decreased DHCR24 protein levels in SH-SY5Y cells in response to Ab 42 treatment are consistent with the literature. ...
  • ... Imbalances in cholesterol homeostasis in the brain can contribute to neurodegenerative diseases such as AD and PD. Additional age-related impairments in glial-derived cholesterol biosynthesis and transport, or uptake of cholesterol by neurons in the brain may adversely affect development, plasticity and synaptic circuitry, and contribute to the inability of the aged brain to sprout new neurites in order to respond to an ever changing environment (Bulloj et al. 2008;Cecchi et al. 2008;Vanmierlo et al. 2009). Because the brain is heavily dependent upon endogenous intracellular cholesterol biosynthesis rather than circulating plasma lipoproteins, understanding how cholesterol is properly utilized to form new neuronal membranes necessary for maintaining proper signalling, growth and expansion may permit us to restore high-order brain function in the aged and neurodegenerative brain through genetic interventions that restore plasmalemmal cholesterol. ...
Electrospray ionization high resolution mass spectrometry (ESI-HRMS) flow injection analyses and bottom-up nanoLC-nanoESI-MS/MS experiments for the molecular characterization of metal complex/biomo…" [more]
The project is aimed at implementing our previous data indicating that oligomer toxicity is a property emerging from a complex interplay between oligomer biophysical properties and the biochemical …" [more]
March 2008 · Neurochemical Research · Impact Factor: 2.59
    A substantial lack of information is recognized on the features underlying the variable susceptibility to amyloid aggregate toxicity of cells with different phenotypes. Recently, we showed that different cell types are variously affected by early aggregates of a prokaryotic hydrogenase domain (HypF-N). In the present study we investigated whether differentiation affects cell susceptibility to... [Show full abstract]
    March 2008 · Journal of Molecular Medicine · Impact Factor: 5.11
      A key role of mitotic activation in neuronal cell death in early stages of Alzheimer's disease (AD) has been suggested. Apparently, terminally differentiated neurons are precluded from mitotic division, yet some phenotypic markers of cell cycling are present in AD-vulnerable brain areas. In this paper, we investigated whether dividing human neuroblastoma cells are preferentially vulnerable to... [Show full abstract]
      July 2010
        IntroductionBiological Surfaces can be Key Triggers of Amyloid Precursor Production, Aggregation, and ToxicityAmyloid Aggregates Display Generic ToxicityShared Biochemical Modifications in Cells Exposed to Toxic AggregatesCellular ContextFinal ConsiderationsReferences
        April 2005 · Journal of endocrinological investigation · Impact Factor: 1.45
          Experimental evidence indicates that estrogen exerts neuroprotective effects. According to the fact that Alzheimer's disease (AD) is more common in post-menopausal women, estrogen treatment has been proposed. However, the beneficial effect of estrogen or selective estrogen receptor modulators (SERMs) in preventing or treating AD is a controversial issue, which will be summarized in this... [Show full abstract]
          Discover more