Lovastatin Induces the Formation of Abnormal Myelin-Like Membrane Sheets in Primary Oligodendrocytes

ArticleinGlia 57(4):402-13 · March 2009with11 Reads
DOI: 10.1002/glia.20769 · Source: PubMed
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.
    • "Given the fact that ApoA-I is expressed at high levels in spinal fluid, and perturbations in lipid metabolism negatively affect myelin, factors that control ApoA-I production and turnover should receive special consideration (Hulshagen et al., 2008; Chrast et al., 2011; Levin et al., 2014). Levels of ApoA-I could be raised with statins, however use of statin medication in MS patients delivered conflicting results (Vollmer et al., 2004; Lock, 2008; Maier et al., 2009; Markovic-Plese et al., 2009; Chataway et al., 2012). A pilot study of 30 MS patients demonstrated a significant decrease in the number and volume of contrast enhancing lesions with 80 mg of simvastatin treatment (Vollmer et al., 2004). "
    [Show abstract] [Hide abstract] ABSTRACT: Jean-Martin Charcot has first described multiple sclerosis (MS) as a disease of the central nervous system (CNS) over a century ago. MS remains incurable today, and treatment options are limited to disease modifying drugs. Over the years, significant advances in understanding disease pathology have been made in autoimmune and neurodegenerative components. Despite the fact that brain is the most lipid rich organ in human body, the importance of lipid metabolism has not been extensively studied in this disorder. In MS, the CNS is under attack by a person’s own immune system. Autoantigens and autoantibodies are known to cause devastation of myelin through up regulation of T-cells and cytokines, which penetrate through the blood–brain barrier to cause inflammation and myelin destruction. The anti-inflammatory role of high-density lipoproteins (HDLs) has been implicated in a plethora of biological processes: vasodilation, immunity to infection, oxidation, inflammation, and apoptosis. However, it is not known what role HDL plays in neurological function and myelin repair in MS. Understanding of lipid metabolism in the CNS and in the periphery might unveil new therapeutic targets and explain the partial success of some existing MS therapies.
    Full-text · Article · Nov 2015
    • "Since Apo A-I is a major HDL component, the use of statin medication could be beneficial. However clinical trials in MS patients delivered controversial results, especially in the area of new relapses and brain plaque formation (Maier et al., 2009; Markovic-Plese et al., 2009; Chataway in wild type and Apo A-I deficient mice. Serum was collected from experimental animals prior to sacrifice on day 36. "
    [Show abstract] [Hide abstract] ABSTRACT: Apolipoprotein A1 (Apo A-I), the most abundant component of high-density lipoprotein (HDL), is an anti-inflammatory molecule, yet its potential role in the pathogenesis of multiple sclerosis (MS) has not been fully investigated. In this study, Western blot analyses of human plasma showed differential Apo A-I expression in healthy controls compared to MS patients. Further, primary progressive MS patients had less plasma Apo A-I than other forms of MS. Using experimental allergic encephalomyelitis (EAE) as a model for MS, Apo A-I deficient mice exhibited worse clinical disease and more neurodegeneration concurrent with increased levels of pro-inflammatory cytokines compared to wild-type animals. These data suggest that Apo A-I plays a role in the pathogenesis of EAE, a model for MS, creating the possibility for agents that increase Apo A-I levels as potential therapies for MS. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Oct 2014
    • "Also in oligodendrocytes LDLR and VLDLR play an important role in the formation of the myelin sheath [35]. Studies have shown that statins, which up-regulate lipid receptors, are not toxic to rat Schwann cells in vitro and that they can induce myelin-like membranes in primary rat oligodendrocytes [36], [37]. Statins can even augment survival and differentiation of oligodendrocytes in an animal model of multiple sclerosis [38]. "
    [Show abstract] [Hide abstract] ABSTRACT: Schwann cell development is hallmarked by the induction of a lipogenic profile. Here we used amniotic fluid stem (AFS) cells and focused on the mechanisms occurring during early steps of differentiation along the Schwann cell lineage. Therefore, we initiated Schwann cell differentiation in AFS cells and monitored as well as modulated the activity of the mechanistic target of rapamycin (mTOR) pathway, the major regulator of anabolic processes. Our results show that mTOR complex 1 (mTORC1) activity is essential for glial marker expression and expression of Sterol Regulatory Element-Binding Protein (SREBP) target genes. Moreover, SREBP target gene activation by statin treatment promoted lipogenic gene expression, induced mTORC1 activation and stimulated Schwann cell differentiation. To investigate mTORC1 downstream signaling we expressed a mutant S6K1, which subsequently induced the expression of the Schwann cell marker S100b, but did not affect lipogenic gene expression. This suggests that S6K1 dependent and independent pathways downstream of mTORC1 drive AFS cells to early Schwann cell differentiation and lipogenic gene expression. In conclusion our results propose that future strategies for peripheral nervous system regeneration will depend on ways to efficiently induce the mTORC1 pathway.
    Full-text · Article · Sep 2014
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