Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM

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, Markus Schwaninger, Erich Gulbins, Martin Reichel, Johannes Kornhuber, Tomoyuki Yamaguchi, Hee Jin Kim, Seung Hyun Kim, Edward H. Schuchman, Hee Kyung Jin*, Jae sung Bae

*Corresponding author for this work
2 Citations (Scopus)


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. Park et al. demonstrate that ASM activity is increased in brain endothelial cells and/or plasma in aged mice, leading to BBB leakage by caveolae-mediated transcytosis via ERM dephosphorylation. Moreover, specific ASM overexpression in brain endothelium accelerates BBB and neuronal dysfunction.

Original languageEnglish
Issue number1
Pages (from-to)167-182
Number of pages16
Publication statusPublished - 10.10.2018

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


Dive into the research topics of 'Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM'. Together they form a unique fingerprint.

Cite this