Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.

Abstract

The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.

• Authors: Yukiko Doi, Hideyuki Takeuchi, Hiroshi Horiuchi, Taketo Hanyu, Jun Kawanokuchi, Shijie Jin, Bijay Parajuli, Yoshifumi Sonobe, Tetsuya Mizuno, Akio Suzumura
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e61988 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23593505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Brain-Derived Neurotrophic Factor
• FTY 720P
• Neuroprotective Agents
• Neurotoxins
• Organophosphates
• Receptors, Lysosphingolipid
• Receptor, trkB
• Extracellular Signal-Regulated MAP Kinases
• Sphingosine

Topics

• Amyloid beta-Peptides (toxicity)
• Animals
• Brain-Derived Neurotrophic Factor (biosynthesis, metabolism)
• Cytoprotection (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Neurons (drug effects, enzymology, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (toxicity)
• Organophosphates (pharmacology)
• Protein Multimerization (drug effects)
• Receptor, trkB (metabolism)
• Receptors, Lysosphingolipid (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)