Ganglioside Hp-s1 Analogue Inhibits Amyloidogenic Toxicity in Alzheimer’s Disease Model Cells
journal contributionposted on 16.10.2018, 00:00 by 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
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.
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AD cell lysatesmonosialoganglioside GM 1amyloid precursor proteinAD model cellsextracellular signal-regulated protein kinaseAPP -695. APP C-terminal fragment -βneurite outgrowth rateAD-modeled cell lineHp-s 1AN 2a mouse neuroblastoma cellsculture media1 μ Mtropomyosin receptor kinaseCTF β levelsIndiana APP geneERKganglioside analogue Hp-s 1AGanglioside Hp-s 1 Analogue Inhibits Amyloidogenic ToxicityHp-s 1A treatment