Abstract：
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age-related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of aging on myelin content in the corpus callosum (CC) and compared aging with the long-term demyelination (LTD) consequents induced by 12 weeks of feeding with a cuprizone (CPZ) diet. Initially, evaluating myelin content in 2-, 6-, and 18-month-old mice revealed a reduction in myelin content, particularly at 18 months. Myelin thickness was decreased and the g-ratio increased in aged mice. Although a lower myelin content and higher g-ratio were observed in LTD model mice, compared to the normally aged mice, both aging and LTD exhibited relatively similar myelin ultrastructure. Our findings provide evidence that LTD exhibits the hallmarks of aging such as elevated expression of senescence-associated genes, mitochondrial dysfunction, and high level of oxidative stress as observed following normal aging. We also investigated the senescence-associated β-galactosidase activity in O4+ late oligodendrocyte progenitor cells (OPCs). The senescent O4+/β-galactosidase+ cells were elevated in the CPZ diet. Our data showed that the myelin degeneration in CC occurs throughout the lifespan, and LTD induced by CPZ accelerates the aging process which may explain the impairment of myelin repair in patients with progressive MS.
摘要：
多发性硬化(MS)是一种影响中枢神经系统的慢性炎性和脱髓鞘疾病。证据表明，年龄相关的神经变性有助于MS慢性阶段的残疾进展。衰老的特征在于脑中的再生潜力降低和髓磷脂修复受损。据推测，加速的细胞衰老有助于与神经退行性疾病相关的功能下降。我们评估了衰老对call体（CC）中髓磷脂含量的影响，并将衰老与用铜锌（CPZ）饮食喂养12周引起的长期脱髓鞘（LTD）结果进行了比较。最初，评估2-髓鞘含量，6-，18个月大的小鼠显示髓鞘含量减少，特别是在18个月。老年小鼠的髓磷脂厚度降低，g比增加。虽然在LTD模型小鼠中观察到较低的髓鞘含量和较高的g比，与正常年龄的老鼠相比，老化和LTD表现出相对相似的髓鞘超微结构。我们的发现提供了证据，表明LTD表现出衰老的标志，例如衰老相关基因的表达升高，线粒体功能障碍，和正常老化后观察到的高水平的氧化应激。我们还研究了O4晚期少突胶质祖细胞（OPC）中与衰老相关的β-半乳糖苷酶活性。CPZ饮食中衰老的O4/β-半乳糖苷酶细胞升高。我们的数据显示，CC中的髓鞘变性在整个生命周期中都会发生，CPZ诱导的LTD加速了衰老过程，这可能解释了进行性MS患者髓鞘修复的损害。
