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

Drug Des Devel Ther. 2022 Mar 30:16:931-950. doi: 10.2147/DDDT.S357061. eCollection 2022.

Abstract

Background: 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.

Keywords: AD; Alzheimer’s disease; HLJDD; HPLC-QTOF-MS; HPLC-QTRAP-MS; Huanglian Jiedu decoction; sphingolipid metabolism.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Ceramides / metabolism
  • Ceramides / therapeutic use
  • Disease Models, Animal
  • Drugs, Chinese Herbal
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Phosphates / therapeutic use
  • Sphingolipids

Substances

  • Amyloid beta-Peptides
  • Ceramides
  • Drugs, Chinese Herbal
  • Phosphates
  • Sphingolipids
  • huanglian-jie-du decoction

Grants and funding

This research was financially supported by the National Natural Science Foundation of China (Project Nos. 81573635 and 81873027), the Qing-Lan Project of Jiangsu Province, the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No. JKLPSE201820), the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Project of the Innovation Research Team of Nanjing University of Chinese Medicine, and the Project Funded by the Six Talent Project in Jiangsu Province.