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Estrogen Depletion Effects on Lipid Homeostasis and Myelination
Holt, Esther
Holt, Esther
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Abstract
Nearly 75% of multiple sclerosis patients are female and have symptoms that improve during pregnancy and worsen during post-menopause, which correlates with changes in estrogen levels within the body.1,2 Studies have shown that the beneficial effects of estrogen on myelination may be attributed to lipid changes in the CNS.1,3 Menopause is associated with worsening symptoms in MS and a decrease in glucose metabolism in the brain which leads to the breakdown of myelin lipids.3 However, the effect of menopause on demyelination and the regulation of myelin lipid pathways has yet to be fully investigated. Our objective is to determine how estrogen loss affects CNS lipid metabolism during demyelination and remyelination. To achieve this goal, we are using the iCKO-Myrf (myelin regulatory factor) mouse strain as a model of demyelination, in which tamoxifen is used to induce ablation of Myrf and initiate demyelination. To mimic menopause, we perform ovariectomies to deplete estrogen prior to inducing demyelination. The experimental groups include ovariectomized females, sham surgery females, control females and control males. Rotarod and horizontal ladder tests are used to monitor motor disability and recovery of mice. Our preliminary results suggest that estrogen depletion accelerates the onset of motor disability after demyelination. Brain and spinal cord tissue will be collected from experimental mice at weeks 12 and 24 post-tamoxifen injection, which represents peak demyelination and remyelination recovery. Myelin and cellular markers of myelin will be analyzed by BlackGold staining, electron microscopy, and immunofluorescence. Lipidomic analysis will be performed using tandem mass spectrometry to measure how phosphatidylcholines, sphingomyelins, phosphatidylserines, and phosphatidylethanolamines are altered with estrogen depletion in demyelination. These studies will define how estrogen loss in the iCKO- Myrf mouse model affects remyelination and CNS lipid metabolism during demyelination. These experiments will enable us to identify mechanisms that mediate the connection between menopause and multiple sclerosis.
References:
1. Rankin, K.; Mei, F.; Kim, K.; Shen, Y.; Mayoral, S.; Desponts, C.; Lorrain, D.; Green, A.; Baranzini, S.; Chan, J.; Bove, R., J. Neurosci. Res., 2019, 39 (12), 2184.
2. Bove, R.; Okai, A.; Houtchens, M.; Elias-Hamp, B.; Lugaresi, A.; Hellwig, K.; Kubala, Havrdová, E., Front. Neurol., 2021, 12, 554375.
3. Voskuhl, R.; Itoh, N.; Tassoni, A.; Matsukawa, M.; Ren, E.; Tse, V.; Jang, E.; Suen, T.; Itoh, Y., PNAS, 2019, 116 (20), 10130.
Description
These are the slides from a presentation given at Pittcon 2025 conference and expo on 03/04/2025.
Date
2025-03-04
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University of Kansas
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Keywords
Menopause, Myelin, Myelination, Mouse model