De Silva Mohotti Nishama, Williams Jenna M, Binjawadagji Rashmi, Kobayashi Hiroko, Dedunupitiya Disni, Petersen Jack M, Garcia Alana, Hartley Meredith D
bioRxiv. 2025 Sep 11:2025.09.06.674663. doi: 10.1101/2025.09.06.674663.
Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases, yet the source of cholesterol ester accumulation and whether it is directly linked to demyelination remains undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and the spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of both acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, suggesting the potential involvement of both proteins in the formation of cholesterol esters. Co-localization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination highlighting the active roles of glia cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.
在患有神经疾病的患者中枢神经系统中已观察到胆固醇酯水平升高，但胆固醇酯积累的来源以及它是否与脱髓鞘直接相关仍不明确。本研究使用Plp1-iCKO-Myrf小鼠模型研究胆固醇酯的时间动态，该模型具有脱髓鞘和髓鞘再生的不同阶段。我们的研究结果表明，大脑和脊髓中的胆固醇酯水平随脱髓鞘而升高。在大脑中，胆固醇酯在髓鞘再生期间降至正常水平，而在脊髓中胆固醇酯仍保持升高，脊髓的髓鞘再生有限。在脱髓鞘期间，乙酰辅酶A-酰基转移酶1（ACAT1）和卵磷脂-胆固醇酰基转移酶（LCAT）的表达均升高，表明这两种蛋白质可能参与胆固醇酯的形成。共定位研究表明，在脱髓鞘期间，ACAT1主要由小胶质细胞表达，LCAT主要由星形胶质细胞表达，突出了神经胶质细胞在胆固醇酯代谢中的积极作用。此外，我们表明，给予髓鞘再生药物Sob-AM2可有效降低脱髓鞘期间大脑中胆固醇酯的积累水平，强调了操纵胆固醇酯调节途径可能为恢复胆固醇稳态和促进脱髓鞘疾病中的髓鞘再生提供的潜力。
