The relationship among amyloid-βdeposition,sphingomyelin level,and the expression and function of P-glycoprotein in Alzheimer’s disease pathological process  

作　　者：Zi-Kang Xing Li-Sha Du Xin Fang Heng Liang Sheng-Nan Zhang Lei Shi Chun-Xiang Kuang Tian-Xiong Han Qing Yang 

机构地区：[1]State Key Laboratory of Genetic Engineering,School of Life Sciences,Shanghai Engineering Research Center of Industrial Microorganisms,Fudan University,Shanghai,China [2]Shanghai Key Lab of Chemical Assessment and Sustainability,School of Chemical Science and Engineering,Tongji University,Shanghai,China [3]Department of Traditional Chinese Medicine,Tenth People’s Hospital of Tongji University,Shanghai,China

出　　处：《Neural Regeneration Research》2023年第6期1300-1307,共8页中国神经再生研究（英文版）

基　　金：supported by the National Key Research and Development Program of China;Nos.2021YFC2 701800 and 2021YFC2 701805 (to QY);Open Research Fund of State Key Laboratory of Genetic Engineering;Fudan University;No.SKLGE-21 19 (to TXH and QY)

摘　　要：In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.

关 键 词：Alzheimer’s disease amyloid-β APP/PS1 mice CERAMIDE ezrin-radixin-moesin human cerebral microvascular endothelial cells neutral sphingomyelinase 1 P-GLYCOPROTEIN sphingomyelin synthase SPHINGOMYELIN 

分 类 号：R749.16[医药卫生—神经病学与精神病学]