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

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Author:: No author available

Journal Title:: Neural Regeneration Research

Issue:: 6

DOI:: No doi available

Key Word:: 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

Abstract： In Alzheimer's disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-β in the brain.Amyloid-β correlates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-β as the central cause of Alzheimer's disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-β and 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.

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