Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM

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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.
Publisher
CELL PRESS
Issue Date
2018-10
Language
English
Article Type
Article
Keywords

BLOOD-BRAIN-BARRIER; ACID SPHINGOMYELINASE/CERAMIDE PATHWAY; CAVEOLAE-MEDIATED TRANSCYTOSIS; ALZHEIMERS-DISEASE; PERMEABILITY; CELLS; CYTOSKELETON; DYSFUNCTION; DISRUPTION; MECHANISMS

Citation

NEURON, v.100, no.1, pp.167 - +

ISSN
0896-6273
DOI
10.1016/j.neuron.2018.09.010
URI
http://hdl.handle.net/10203/246547
Appears in Collection
BiS-Journal Papers(저널논문)
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