Drug Design, Development and Therapy (Mar 2022)

Involvement of Huanglian Jiedu Decoction on Microglia with Abnormal Sphingolipid Metabolism in Alzheimer’s Disease

  • Qi YY,
  • Heng X,
  • Yao ZY,
  • Qu SY,
  • Ge PY,
  • Zhao X,
  • Ni S,
  • Guo R,
  • Yang NY,
  • Zhang QC,
  • Zhu HX

Journal volume & issue
Vol. Volume 16
pp. 931 – 950

Abstract

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Yi-Yu Qi,1,* Xia Heng,1,* Zeng-Ying Yao,2 Shu-Yue Qu,1 Ping-Yuan Ge,1 Xin Zhao,1 Sai-jia Ni,2 Rui Guo,3 Nian-Yun Yang,1 Qi-Chun Zhang,2 Hua-Xu Zhu1 1Department of Traditional Chinese Medicine Processing and Preparation, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Department of Physiological, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi-Chun Zhang; Hua-Xu Zhu, Email [email protected]; [email protected]: Abnormal sphingolipid metabolism is closely related to the occurrence and development of Alzheimer’s disease (AD). With heat-clearing and detoxifying effects, Huanglian Jiedu decoction (HLJDD) has been used to treat dementia and improve learning and memory impairments.Purpose: To study the therapeutic effect of HLJDD on AD as it relates to sphingolipid metabolism.Methods: The level of sphingolipids in the brains of APP/PS1 mice and in the supernatant of β-amyloid (Aβ)25– 35-induced BV2 microglia was detected by HPLC-QTOF-MS and HPLC-QTRAP-MS techniques, respectively. The co-expression of ionized calcium-binding adapter molecule 1 (Iba1) and Aβ as well as four enzymes related to sphingolipid metabolism, including serine palmitoyltransferase 2 (SPTLC2), cer synthase 2 (CERS2), sphingomyelin phosphodiesterase 1 (SMPD1), and sphingomyelin synthase 1 (SGMS1), in the brains of APP/PS1 mice were evaluated by immunofluorescence double labelling. In addition, real-time quantitative reverse transcription-polymerase chain reaction was conducted to determine the mRNA expression of SPTLC2, CERS2, SMPD1, SGMS1, galactosylceramidase (GALC), and sphingosine kinase 2 (SPHK2) in Aβ25-35-stimulated BV2 microglia.Results: Abnormal sphingolipid metabolism was observed both in APP/PS1 mouse brain tissues and Aβ25-35-stimulated BV2 cells. The levels of sphingosine, sphinganine, sphingosine-1-phosphate, sphinganine-1-phosphate and sphingomyelin were significantly reduced, while the levels of ceramide-1-phosphate, ceramide, lactosylceramide and hexosylceramide significantly increased in Aβ25-35-stimulated BV2 cells. In AD mice, more microglia were clustered in the Aβ-positive region. The decreased level of SGMS1 and increased levels of CERS2, SPTLC and SMPD1 were also found. In addition, the expressions of SPTLC2, CERS2, and SMPD1 in Aβ25-35-stimulated BV2 cells were increased significantly, while the expressions of GALC, SPHK2, and SGMS1 were decreased. These changes all showed a significant correction after HLJDD treatment.Conclusion: HLJDD is a good candidate for treating AD. This study provides a novel perspective on the potential roles of the sphingolipid metabolism in AD.Graphical Abstract: Keywords: Huanglian Jiedu decoction, HLJDD, Alzheimer’s disease, AD, sphingolipid metabolism, HPLC-QTOF-MS, HPLC-QTRAP-MS

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