Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM

Park MH, Lee JY, Park KH, Jung IK, Kim KT, Lee YS, Ryu HH, Jeong Y, Kang M, Schwaninger M, Gulbins E, Reichel M, Kornhuber J, Yamaguchi T, Kim HJ, Kim SH, Schuchman EH, Jin HK, Bae JS (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Neuron Elsevier (Cell Press)

Book Volume: 100

Pages Range: 167-182.e9

Journal Issue: 1

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.

Authors with CRIS profile

Martin Reichel Department of Medicine 4 – Nephrology and Hypertension Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie

Involved external institutions

University of Tokyo JP Japan (JP) Hanyang University / 한양대학교 KR Korea, Republic of (KR) Icahn School of Medicine at Mount Sinai US United States (USA) (US) Kyungpook National University KR Korea, Republic of (KR) Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Korea Advanced Institute of Science and Technology (KAIST) KR Korea, Republic of (KR) Universität zu Lübeck DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE)

How to cite

APA:

Park, M.H., Lee, J.Y., Park, K.H., Jung, I.K., Kim, K.-T., Lee, Y.-S.,... Bae, J.-S. (2018). Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM. Neuron, 100(1), 167-182.e9. https://doi.org/10.1016/j.neuron.2018.09.010

MLA:

Park, Min Hee, et al. "Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM." Neuron 100.1 (2018): 167-182.e9.

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