Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.
Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.
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DOI：
10.1371/journal.pone.0061988
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Suzumura A
中科院分区：
文献类型：
--
作者：
Doi Y;Takeuchi H;Horiuchi H;Hanyu T;Kawanokuchi J;Jin S;Parajuli B;Sonobe Y;Mizuno T;Suzumura A
阿尔茨海默病的神经退行性过程部分由可溶性寡聚淀粉样蛋白β介导，这是一种神经毒性蛋白，可抑制海马长时程增强，破坏突触可塑性，并诱导活性氧的产生。在这里，我们表明，鞘氨醇-1-磷酸（S1 P）受体（S1 PR）激动剂磷酸芬戈莫德（FTY 720-P）-一种新的口服多发性硬化症药物-保护神经元免受寡聚淀粉样蛋白β诱导的神经毒性。我们证实，原代小鼠皮层神经元表达所有的S1 P受体亚型和FTY 720-P直接影响神经元。FTY 720-P处理可增强神经元中脑源性神经营养因子（BDNF）的表达。此外，用BDNF清除剂、TrkB抑制剂或ERK 1/2抑制剂阻断BDNF-TrkB信号传导几乎完全消除了这些神经保护作用。这些结果表明，FTY 720-P的神经保护作用是通过上调神经元BDNF水平介导的。因此，FTY 720-P可能是一种有前途的神经退行性疾病，如阿尔茨海默病的治疗剂。
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.
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