| First Author | Park MH | Year | 2018 |
| Journal | Neuron | Volume | 100 |
| Issue | 1 | Pages | 167-182.e9 |
| PubMed ID | 30269989 | Mgi Jnum | J:269360 |
| Mgi Id | MGI:6269328 | Doi | 10.1016/j.neuron.2018.09.010 |
| Citation | Park MH, et al. (2018) Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM. Neuron 100(1):167-182.e9 |
| abstractText | 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. |
