Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease
Astrocytic connexin 43 potentiates myelin injury in ischemic white matter disease
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星形细胞连接蛋白 43 增强缺血性白质疾病中的髓磷脂损伤
DOI：
10.7150/thno.31942
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Wang, Minghuan;Qin, Chuan;Wang, Wei
理由：髓磷脂损失是缺血性白色疾病及其相关血管性痴呆的特征性特征，并且是由于颈动脉狭窄引起的慢性脑灌注不足的标志。然而，涉及缺血性髓鞘形成障碍的细胞机制尚未得到很好的理解，也没有有效的治疗方法来预防或减缓低灌注相关的脱髓鞘。在一项采用双侧颈总动脉狭窄（BCAS）小鼠模型的研究中，我们发现脑血流速度和小动脉脉动性降低，并证实延长BCAS引起髓鞘破坏。这些病理特征与明显的认知能力下降有关，而轴突没有明显的损伤。研究方法：为了评估星形胶质细胞通讯在BCAS相关脱髓鞘中的作用，我们研究了删除或抑制连接蛋白43（Cx43）的作用，Cx43是星形胶质细胞间隙连接和半通道的组成部分。结果如下：间隙连接的遗传缺失和药理学抑制既保护了髓鞘的完整性，又挽救了BCAS治疗小鼠的认知能力下降。缝隙连接抑制也抑制了在接触BCAS的野生型小鼠胼胝体白色物质中观察到的细胞外谷氨酸的瞬时增加。结论：这些发现表明，星形胶质细胞Cx43可能是一个可行的目标，减轻与慢性脑灌注不足相关的脱髓鞘和认知能力下降。
Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons. Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels. Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS. Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.