title: 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.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Doi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Taketo
authors.initials: T
authors.lastname: Hanyu
authors.forename: Jun
authors.initials: J
authors.lastname: Kawanokuchi
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.forename: Bijay
authors.initials: B
authors.lastname: Parajuli
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sonobe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D010755:Organophosphates / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D020813:Receptor, trkB / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; C525008:FTY 720P; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010755:Organophosphates; D049349:Receptors, Lysosphingolipid; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine