Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer's Disease Model Cells

Yow Fu Tsai, Dun Jhu Yang, Thi Huong Ngo, Cheng Hua Shih, Yu Fa Wu, Ching Kuo Lee, Veerapol Phraekanjanavichid, Shu Fen Yen, Shu Huei Kao, Horng Mo Lee, Vivian Shuhsien Huang, Jonathan Chang Cheng Shieh, Yung Feng Lin

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4 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-β (Aβ) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1's analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 μM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFβ levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aβ42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.

Original languageEnglish
Pages (from-to)528-536
Number of pages9
JournalACS Chemical Neuroscience
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 16 2019

Keywords

  • Alzheimer's disease
  • amyloid precursor protein
  • amyloid-β
  • amyloidogenesis
  • ganglioside
  • Hp-s1
  • Hp-s1A
  • neuritogenesis
  • neurotrophic signaling

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Tsai, Y. F., Yang, D. J., Ngo, T. H., Shih, C. H., Wu, Y. F., Lee, C. K., Phraekanjanavichid, V., Yen, S. F., Kao, S. H., Lee, H. M., Huang, V. S., Shieh, J. C. C., & Lin, Y. F. (2019). Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer's Disease Model Cells. ACS Chemical Neuroscience, 10(1), 528-536. https://doi.org/10.1021/acschemneuro.8b00406