Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Molecular and Applied Biology Research Unit, University of Florence, Viale GB Morgagni 50, 5134 Firenze, Italy; Interuniversitary Miology Institutes, Italy.
Department of Biology, University of Pisa, Via San Zen, 31, 56127 Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy.
Neuropharmacology. 2017 Apr;116:328-342. doi: 10.1016/j.neuropharm.2017.01.003. Epub 2017 Jan 7.
Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)D), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)D We have found that 1,25(OH)D prevents amyloid-β peptide (Aβ(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Aβ(1-42) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)D partially reverts this effect. 1,25(OH)D reverts also the Aβ(1-42)-induced reduction of sphingosine kinase activity. We have also studied the crosstalk between 1,25(OH)D and S1P signaling pathways downstream to the activation of S1P receptor subtype S1P1. Notably, we found that 1,25(OH)D prevents the reduction of S1P1 expression promoted by Aβ(1-42) and thereby it modulates the downstream signaling leading to ER stress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronic treatment with 1,25(OH)D protects from aggregated Aβ(1-42)-induced damage in the CA1 region of the rat hippocampus and promotes cell proliferation in the hippocampal dentate gyrus of adult mice. In conclusion, these results represent the first evidence of the role of 1,25(OH)D and its structural analogue ZK191784 in counteracting the Aβ(1-42) peptide-induced toxicity through the modulation of S1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.
除了其经典的骨代谢调节功能外，1α，25-二羟维生素 D3（1,25（OH）D）还作用于包括神经系统在内的多种组织，在神经系统中，该激素作为神经保护、抗增殖和分化剂发挥着重要作用。神经鞘脂是生物活性脂质，在调节细胞命运方面发挥着关键而复杂的作用。在本文中，我们研究了神经鞘脂是否参与 1,25（OH）D 的保护作用。我们发现 1,25（OH）D 可预防淀粉样β肽（Aβ（1-42））在分化的 SH-SY5Y 人神经母细胞瘤细胞中和体内的细胞毒性。在分化的 SH-SY5Y 细胞中，Aβ（1-42）强烈降低了神经鞘氨醇-1-磷酸（S1P）/神经酰胺（Cer）的比例，而 1,25（OH）D 部分逆转了这种作用。1,25（OH）D 还逆转了 Aβ（1-42）诱导的神经鞘氨醇激酶活性降低。我们还研究了 1,25（OH）D 与 S1P 信号通路之间的串扰，该信号通路位于 S1P 受体亚型 S1P1 的激活之后。值得注意的是，我们发现 1,25（OH）D 可防止 Aβ（1-42）促进的 S1P1 表达降低，从而调节导致内质网应激损伤（p38MAPK/ATF4）的下游信号。使用 ZK191784 也观察到了类似的效果。此外，慢性 1,25（OH）D 治疗可防止大鼠海马 CA1 区聚集的 Aβ（1-42）诱导的损伤，并促进成年小鼠海马齿状回的细胞增殖。总之，这些结果首次证明了 1,25（OH）D 及其结构类似物 ZK191784 通过调节 S1P/S1P1/p38MAPK/ATF4 通路在分化的 SH-SY5Y 细胞中发挥作用，从而抵消 Aβ（1-42）肽诱导的毒性。
