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Acid sphingomyelinase-mediated blood-brain barrier disruption in aging
Jae-sung Bae1,*, Hee Kyung Jin1, Min Hee Park1
1Alzheimer’s disease Research Institute, Kyungpook National University, Daegu 41566, Korea,
2Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea,
3Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Korea,
4Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
Although many studies have reported that the breakdown of the blood-brain barrier (BBB) represents one of the major pathological changes in aging, the mechanism underlying this process remains relatively unexplored. In this study, we described that acid sphingomyelinase (ASM) derived from endothelial cells plays a critical role in BBB disruption in aging. ASM levels were elevated in the brain endothelium and plasma of aged humans and mice, resulting in BBB leakage through an increase in caveolae-mediated transcytosis. Moreover, ASM caused damage to the caveolae-cytoskeleton via protein phosphatase 1-mediated ezrin/radixin/moesin dephosphorylation in primary mouse brain endothelial cells. Mice overexpressing brain endothelial cell-specific ASM exhibited acceleration of BBB impairment and neuronal dysfunction. However, genetic inhibition and endothelial specific knock-down of ASM in mice improved BBB disruption and neurocognitive impairment during aging. Results of this study revealed a novel role of ASM in the regulation of BBB integrity and neuronal function in aging, thus highlighting the potential of ASM as a new therapeutic target for anti-aging.
Abstract, Accepted Manuscript [Submitted on January 30, 2019, Accepted on January 30, 2019]
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