Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0061988
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Funding
- Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO)
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan
- Grants-in-Aid for Scientific Research [24111520] Funding Source: KAKEN
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The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid beta, 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 beta-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.
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