Lovastatin induces the formation of abnormal myelin-like membrane sheets in primary oligodendrocytes
ABSTRACT Statins, well-known inhibitors of cholesterol synthesis and protein isoprenylation, have been proposed as therapeutic drugs for multiple sclerosis (MS). As lovastatin and simvastatin, which are currently tested for their use in MS, can cross the blood-brain barrier, they may affect cellular processes in the central nervous system. This is especially relevant with respect to remyelination as a proposed additional treatment for MS, because cholesterol is a major component of myelin. Here, we show that primary oligodendrocytes, treated with lovastatin, form extensive membrane sheets, which contain galactosphingolipids. However, these membrane sheets are devoid of the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Reduced MBP protein expression was confirmed by SDS-PAGE and Western blotting, and in situ hybridization experiments revealed that lovastatin blocks MBP mRNA transport into oligodendrocyte processes. In contrast, PLP expression was only mildly affected by lovastatin. However, lovastatin treatment resulted in intracellular accumulation of PLP and prevented its translocation to the cell surface. Interestingly, another inhibitor of cholesterol synthesis (ro48-8071), which does not interfere with isoprenylation, had a similar effect on the localization of PLP, but it did not affect MBP expression and localization. These results suggest that lovastatin affects PLP transport predominantly by the inhibition of cholesterol synthesis, whereas reduced MBP expression is caused by impaired isoprenylation. Based on these results we recommend to carefully monitor the effect of statins on myelination prior to their use in demyelinating diseases.
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ABSTRACT: Accumulating evidence indicates that white matter degeneration contributes to the neural disconnections that underlie Alzheimer's disease pathophysiology. Although this white matter degeneration is partly attributable to axonopathy associated with neuronal degeneration, amyloid β (Aβ) protein-mediated damage to oligodendrocytes could be another mechanism. To test this hypothesis, we studied effects of soluble Aβ in oligomeric form on survival and differentiation of cells of the oligodendroglial lineage using highly purified oligodendroglial cultures from rats at different developmental stages. Aβ oligomer at 10 μM or higher reduced survival of mature oligodendrocytes, whereas oligodendroglial progenitor cells (OPCs) were relatively resistant to the Aβ oligomer-mediated cytotoxicity. Further study revealed that Aβ oligomer even at 1 μM accelerated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis in mature oligodendrocytes, and, more significantly, inhibited myelin sheet formation after induction of in vitro differentiation of OPCs. These results imply a novel pathogenetic mechanism underlying Aβ oligomer-mediated white matter degeneration, which could impair myelin maintenance and remyelination by adult OPCs, resulting in accumulating damage to myelinating axons thereby contributing to neural disconnections.Neurobiology of aging 03/2012; 33(3):499-509. DOI:10.1016/j.neurobiolaging.2010.05.007 · 4.85 Impact Factor
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ABSTRACT: Previously, we and others documented that statins including-lovastatin (LOV) promote the differentiation of oligodendrocyte progenitor cells (OPCs) and remyelination in experimental autoimmune encephalomyelitis (EAE), an multiple sclerosis (MS) model. Conversely, some recent studies demonstrated that statins negatively influence oligodendrocyte (OL) differentiation in vitro and remyelination in a cuprizone-CNS demyelinating model. Therefore, herein, we first investigated the cause of impaired differentiation of OLs by statins in vitro settings. Our observations indicated that the depletion of cholesterol was detrimental to LOV treated OPCs under cholesterol/serum-deprived culture conditions similar to that were used in conflicting studies. However, the depletion of geranylgeranyl-pp under normal cholesterol homeostasis conditions enhanced the phenotypic commitment and differentiation of LOV-treated OPCs ascribed to inhibition of RhoA-Rho kinase. Interestingly, this effect of LOV was associated with increased activation and expression of both PPAR-γ and PTEN in OPCs as confirmed by various pharmacological and molecular based approaches. Furthermore, PTEN was involved in an inhibition of OPCs proliferation via PI3K-Akt inhibition and induction of cell cycle arrest at G1 phase, but without affecting their cell survival. These effects of LOV on OPCs in vitro were absent in the CNS of normal rats chronically treated with LOV concentrations used in EAE indicating that PPAR-γ induction in normal brain may be tightly regulated-providing evidences that statins are therapeutically safe for humans. Collectively, these data provide initial evidence that statin-mediated activation of the PPAR-γ-PTEN cascade participates in OL differentiation, thus suggesting new therapeutic-interventions for MS or related CNS-demyelinating diseases.Glia 11/2010; 58(14):1669-85. DOI:10.1002/glia.21039 · 6.03 Impact Factor
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ABSTRACT: In the central nervous system, a multilayered membrane layer known as the myelin sheath enwraps axons, and is required for optimal saltatory signal conductance. The sheath develops from membrane processes that extend from the plasma membrane of oligodendrocytes and displays a unique lipid and protein composition. Myelin biogenesis is carefully regulated, and multiple transport pathways involving a variety of endosomal compartments are involved. Here we briefly summarize how the major myelin proteins proteolipid protein and myelin basic protein reach the sheath, and highlight potential mechanisms involved, including the role of myelin specific lipids and cell polarity related transport pathways.FEBS letters 11/2009; 584(9):1760-70. DOI:10.1016/j.febslet.2009.10.085 · 3.34 Impact Factor