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

• Published in: PloS one 2013-04, Vol.8 (4), p.e61988
• Main Authors: Doi, Yukiko, Takeuchi, Hideyuki, Horiuchi, Hiroshi, Hanyu, Taketo, Kawanokuchi, Jun, Jin, Shijie, Parajuli, Bijay, Sonobe, Yoshifumi, Mizuno, Tetsuya, Suzumura, Akio
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; Biology; Brain; Brain research; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - biosynthesis; Brain-Derived Neurotrophic Factor - metabolism; Chemical compounds; Cytoprotection - drug effects; Environmental health; Extracellular Signal-Regulated MAP Kinases - metabolism; FTY720; Gene expression; Hippocampal plasticity; Hippocampus; Humans; Inhibitors; Kinases; Long-term potentiation; Lymphocytes; MAP Kinase Signaling System - drug effects; Medical research; Medicine; Memory; Mice; Multiple sclerosis; Nervous system; Neurodegenerative diseases; Neurological diseases; Neurons; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; Neurotoxicity; Neurotoxins - toxicity; Organophosphates - pharmacology; Oxygen; Pharmacology; Phosphates; Protein Multimerization - drug effects; Proteins; Reactive oxygen species; Receptor, trkB - metabolism; Receptors, Lysosphingolipid - metabolism; Rodents; Signaling; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Sphingosine 1-phosphate; Synaptic plasticity; TrkB receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061988

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.