Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASMopen access
- Authors
- Park, Min Hee; Lee, Ju Youn; Park, Kang Ho; Jung, In Kyung; Kim, Kyoung-Tae; Lee, Yong-Seok; Ryu, Hyun-Hee; Jeong, Yong; Kang, Minseok; Schwaninger, Markus; Gulbins, Erich; Reichel, Martin; Kornhuber, Johannes; Yamaguchi, Tomoyuki; Kim, Hee Jin; Kim, Seung Hyun; Schuchman, Edward H.; Jin, Hee Kyung; Bae, Jae-Sung
- Issue Date
- Oct-2018
- Publisher
- CELL PRESS
- Keywords
- acid sphingomyelinase; aging; blood-brain barrier; caveolae; neural function
- Citation
- NEURON, v.100, no.1, pp.167 - 182
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEURON
- Volume
- 100
- Number
- 1
- Start Page
- 167
- End Page
- 182
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/149284
- DOI
- 10.1016/j.neuron.2018.09.010
- ISSN
- 0896-6273
- Abstract
- 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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