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Multiple sclerosis cuprizone mouse model and vitamin D supplementation

ABSTRACT: Dietary supplementation of vitamin D is commonly recommended to patients with multiple sclerosis (MS). We investigated the effect of 1,25-dihydroxyvitamin-D3 (1,25-(OH)2D3) on the brain proteome in the cuprizone model during remyelination. Mice were demyelinated with dietary cuprizone for 7 weeks. The mice received intra-peritoneal injections of 1,25-(OH)2D3 or placebo twice a week, from week 6 and throughout week 10. Brain samples were taken after 7 weeks (demyelinated), after 8 weeks (1 week remyelination) and after 10 weeks (3 weeks of remyelination). The six experimental groups were labeled with TMT, mixed mode HPLC fractionation, and applied to LC-MS which enabled quantification of 5062 proteins with high confidence.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Multiple Sclerosis

SUBMITTER: Eystein Oveland

LAB HEAD: Frode Berven

PROVIDER: PXD002347 | Pride | 2017-08-16

REPOSITORIES: Pride

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			Action	DRS
	CPZ_VitD_7_8_10weeks_TMT6plex_PD_pepeptides_2016.xlsx	Xlsx
	TMT6_frac_10.raw	Raw
	TMT6_frac_11.raw	Raw
	TMT6_frac_12.raw	Raw
	TMT6_frac_13.raw	Raw

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Publications

1,25-Dihydroxyvitamin-D3 induces brain proteomic changes in cuprizone mice during remyelination involving calcium proteins.

Oveland Eystein E Nystad Agnes A Berven Frode F Myhr Kjell-Morten KM Torkildsen Øivind Ø Wergeland Stig S

Neurochemistry international 20170814

Dietary supplementation of vitamin D is commonly recommended to patients with multiple sclerosis. We recently found that high-dose of the hormonally active 1,25-dihydroxyvitamin-D<sub>3</sub> (1,25D) promotes myelin repair in the cuprizone model for de- and remyelination. In the present study, we quantified 5062 proteins, of which 125 were differentially regulated in brain tissue from 1,25D treated mice during remyelination, compared to placebo. Proteins upregulated in the early remyelination ph ...[more]

PMID: 28818673

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Fingolimod and remyelination - Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model

Project description:Remyelinating substances could be an essential supplement to immunomodulatory medications, optimizing the treatment of multiple sclerosis (MS) patients. Fingolimod is a sphingosine-1-phosphate receptor (S1PR) modulator and crosses the blood-brain barrier. Central nervous system (CNS) cells express S1PRs, and Fingolimod could theoretically improve CNS remyelination and be neuroprotective per se, but data are inconsistent. We used the cuprizone model for investigating the effect of fingolimod on remyelination and axonal damage by Immunohistochemistry and quantitative mass spectrometry. After three weeks of remyelination, fingolimod-treated mice had more mature oligodendrocytes in the secondary motor cortex than the placebo group. However, fingolimod did not at any time point affect remyelination or axonal damage. We conclude that fingolimod does not promote remyelination or protect against axonal injury or loss after cuprizone exposure.

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Dynamics of reactive astrocytes fosters tissue regeneration after cuprizone-induced demyelination [RNA-seq II]

Project description:Demyelination and dysregulated myelination in the CNS are hallmarks of many neurodegenerative diseases such as multiple sclerosis (MS) and leukodystrophies. Here, we studied GFAP+ astrocytes during de- and remyelination in the cuprizone mouse by exploiting the ribosomal tagging (RiboTag) technology. Analyses were performed 5 weeks after cuprizone feeding, at the peak of demyelination in the corpus callosum, and 0.5 and 2 weeks after cuprizone withdrawal, when remyelination and tissue repair is initiated. After 5 weeks of cuprizone feeding, reactive astrocytes showed inflammatory signatures with enhanced expression of genes that modulate leukocyte migration (Tlr2, Cd86, Parp14,Cxcl10). Furthermore, demyelination-induced reactive astrocytes expressed numerous ligands including Cx3cl1, Csf1, Il34, and Gas6 that act on homeostatic as well as activated microglia and thus potentially mediate activation and recruitment of microglia as well as enhancement of their phagocytosis. During early remyelination, region-specific astrocytes displayed reduced inflammatory response signatures as indicated by shut down of CXCL10 production. During late remyelination, the signatures of GFAP+ astrocytes shifted towards resolving inflammation by active suppression of lymphocyte activation and differentiation and support of glia cell differentiation. Astrocytes showed enhanced expression of osteopontin (SPP1) as well as of factors that are relevant for tissue remodelling (Timp1), regeneration and axonal repair. In conclusion, we detected highly dynamic astroglial transcriptomic signatures in the cuprizone model, which reflects excessive communication amongst glia cells and highlights different astrocyte functions during neurodegeneration and regeneration.

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Expression data from white matter astrocytes of wild-type or GnT-IX-deficient mice after cuprizone administration

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