酸性鞘磷脂酶
小窝
跨细胞
细胞生物学
血脑屏障
内皮
放射毒素
神经科学
小窝蛋白1
内皮功能障碍
生物
内分泌学
内科学
神经发生
冲程(发动机)
信号转导
鞘磷脂
细胞骨架
内吞作用
中枢神经系统
埃兹林
胆固醇
细胞
遗传学
作者
Min Hee Park,Ju Youn Lee,Kang Ho Park,In Kyung Jung,Kyoung-Tae Kim,Yong Seok Lee,Hyun Hee Ryu,Yong Jeong,Minseok Kang,Ari Waisman,Erich Gulbins,Martin Reichel,Johannes Kornhuber,Tomoyuki Yamaguchi,Hee Jin Kim,Seung Hyun Kim,Edward H. Schuchman,Hee Kyung Jin,Jae-sung Bae
出处
期刊:Neuron
[Elsevier]
日期:2018-10-10
卷期号:100 (1): 167-182.e9
被引量:23
标识
DOI:10.1016/j.neuron.2018.09.010
摘要
Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.
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