Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (6): 1300-1307.doi: 10.4103/1673-5374.358607

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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

Zi-Kang Xing1, Li-Sha Du1, Xin Fang1, Heng Liang1, Sheng-Nan Zhang1, Lei Shi1, Chun-Xiang Kuang2, Tian-Xiong Han3, Qing Yang1, *   

  1. 1State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China; 2Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai, China; 3Department of Traditional Chinese Medicine, Tenth People’s Hospital of Tongji University, Shanghai, China
  • Online:2023-06-15 Published:2023-01-05
  • Contact: Qing Yang, PhD, yangqing68@fudan.edu.cn.
  • Supported by:
    This work was supported by the National Key Research and Development Program of China, Nos. 2021YFC2701800 and 2021YFC2701805 (to QY) and Open Research Fund of State Key Laboratory of Genetic Engineering, Fudan University, No. SKLGE-2119 (to TXH and QY).

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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.

Key words: 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