Mather Marie L, Evangelou Angelina V, Bourne Jennifer N, Macklin Wendy B, Wood Teresa L
Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Glia. 2025 Sep;73(9):1841-1859. doi: 10.1002/glia.70042. Epub 2025 May 26.
Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.
胆固醇在髓鞘中高度富集，并且在影响髓鞘完整性的神经退行性疾病中常常失调。尽管针对甾醇合成的促髓鞘形成药物很突出，而且我们对少突胶质细胞异质性的了解也越来越多，但很少有研究明确中枢神经系统中脂质代谢的区域差异。先前的分析表明，与脑少突胶质细胞相比，脊髓少突胶质细胞内源性胆固醇生物合成能力更高。我们目前的研究结果表明，与脊髓少突胶质细胞相反，脑少突胶质细胞摄取和响应细胞外脂蛋白的能力更高。此外，脑髓磷脂的脂质浓度低于脊髓髓磷脂。脊髓与脑各亚区域之间的比较表明，髓磷脂脂质含量与平均轴突直径相关，因此轴突直径较小的区域，如胼胝体和皮质灰质，其髓磷脂的胆固醇和磷脂含量低于包含较大直径轴突的区域，包括脊髓和脑干。当在体外合成纳米纤维上分化时，无论纤维直径如何，脊髓少突胶质细胞的胆固醇含量都高于脑少突胶质细胞，但脂肪酸含量显示出纤维直径依赖性变化。雷帕霉素机制靶点（mTOR）信号传导支持髓磷脂组成区域差异的建立和维持，因为少突胶质细胞中mTOR的缺失消除了髓磷脂脂质含量的区域差异，脊髓和脑干中的下降最为明显。这些数据突出了脑和脊髓脂质代谢的多种差异，这些差异导致了区域上不同的髓磷脂组成。
