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

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.

The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

“…In addition, administration of naked GM1 can decrease binding of amyloid fragments to neuronal lipid rafts [ 156 ]. Moreover, gangliosides may inhibit amyloidogenic processing of APP [ 180 ].…”

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells

“…It is worth noting that Hp-s1 alone increased the phosphorylation of ERK in microglial cells. Several previous studies reported that some gangliosides increase the phosphorylation of ERK, such as GM1 [ 36 ], Hp-s1 analog [ 23 ], and GM3 [ 37 ]. Increase in phosphorylation of ERK by Hp-s1 might explain why Hp-s1 cannot inhibit ERK activity in LPS-stimulated microglia.…”

“…The neuritogenic activity of Hp-s1 and its synthetic analogs is better than that of GM1 ganglioside in PC-12 cells [ 22 ]. Moreover, Hp-s1 analog inhibits amyloidogenic toxicity in model cells of Alzheimer’s disease [ 23 ]. However, the effects of Hp-s1 on neuroinflammation are still unknown.…”

Protective Evaluation of Compounds Extracted from Root of Rhodiola rosea L. against Methylglyoxal-Induced Toxicity in a Neuronal Cell Line

“…N2A cells (ATCC, CCL-131) were maintained in minimum essential medium (Eagle) with 2 mM L-glutamine, 0.1 mM non-essential amino acids, 1.5 g/L sodium bicarbonate, and 1.0 mM sodium pyruvate (Life Technologies, Carlsbad, CA, United States), supplemented with 10% heat-inactivated fetal bovine serum (Life Technologies), 100 units/mL penicillin, 100 μg/mL streptomycin, and 2.5 μg/mL amphotericin B (Life Technologies) as indicated [ 51 , 52 ]. Cultures were incubated at 37 °C with 5% CO 2 in a humidified incubator.…”