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

doi:10.1016/j.neuron.2018.09.010

Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM

Neuron. 2018 Oct 10;100(1):167-182.e9. doi: 10.1016/j.neuron.2018.09.010. Epub 2018 Sep 27.

Authors

Min Hee Park¹, Ju Youn Lee¹, Kang Ho Park¹, In Kyung Jung¹, Kyoung-Tae Kim², Yong-Seok Lee³, Hyun-Hee Ryu⁴, Yong Jeong⁵, Minseok Kang⁵, Markus Schwaninger⁶, Erich Gulbins⁷, Martin Reichel⁸, Johannes Kornhuber⁸, Tomoyuki Yamaguchi⁹, Hee-Jin Kim¹⁰, Seung Hyun Kim¹⁰, Edward H Schuchman¹¹, Hee Kyung Jin¹², Jae-Sung Bae¹³

Affiliations

¹ Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea; Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea; Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea.
² Department of Neurosurgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea.
³ Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
⁴ Department of Physiology, Seoul National University College of Medicine, Seoul, Korea; Department of Life Science, Chung-Ang University, Seoul, Korea.
⁵ Department of Bio and Brain Engineering, Korea Advance Institute of Science and Technology, Daejeon, Korea.
⁶ Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
⁷ Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
⁸ Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
⁹ Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
¹⁰ Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea; Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea. Electronic address: hkjin@knu.ac.kr.
¹³ Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea; Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea; Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea. Electronic address: jsbae@knu.ac.kr.

PMID: 30269989
DOI: 10.1016/j.neuron.2018.09.010

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.

Keywords: acid sphingomyelinase; aging; blood-brain barrier; caveolae; neural function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Aging / metabolism*
Animals
Blood-Brain Barrier / enzymology*
Blood-Brain Barrier / pathology*
Endothelial Cells / enzymology
Endothelial Cells / pathology
Female
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Rejuvenation / physiology*
Sphingomyelin Phosphodiesterase / metabolism*
Young Adult

Substances

Sphingomyelin Phosphodiesterase