Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3(1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays animportant role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactivelipids that play critical and complex roles in regulating cell fate. In the present paper we have investigatedwhether sphingolipids are involved in the protective action of 1,25(OH)2D3. We have found that1,25(OH)2D3 prevents amyloid-b peptide (Ab(142)) cytotoxicity both in differentiated SH-SY5Y humanneuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Ab(142) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)2D3 partially reverts this effect.1,25(OH)2D3 reverts also the Ab(142)-induced reduction of sphingosine kinase activity. We have alsostudied the crosstalk between 1,25(OH)2D3 and S1P signaling pathways downstream to the activation ofS1P receptor subtype S1P1. Notably, we found that 1,25(OH)2D3 prevents the reduction of S1P1expression promoted by Ab(142) and thereby it modulates the downstream signaling leading to ERstress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronictreatment with 1,25(OH)2D3 protects from aggregated Ab(142)-induced damage in the CA1 region ofthe 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)2D3 and its structuralanalogue ZK191784 in counteracting the Ab(142) peptide-induced toxicity through the modulation ofS1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.
Vitamin D3 protects against Ab peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis
Eleonora Vannini;Marco Mainardi;Matteo Caleo;
2017
Abstract
Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3(1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays animportant role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactivelipids that play critical and complex roles in regulating cell fate. In the present paper we have investigatedwhether sphingolipids are involved in the protective action of 1,25(OH)2D3. We have found that1,25(OH)2D3 prevents amyloid-b peptide (Ab(142)) cytotoxicity both in differentiated SH-SY5Y humanneuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Ab(142) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)2D3 partially reverts this effect.1,25(OH)2D3 reverts also the Ab(142)-induced reduction of sphingosine kinase activity. We have alsostudied the crosstalk between 1,25(OH)2D3 and S1P signaling pathways downstream to the activation ofS1P receptor subtype S1P1. Notably, we found that 1,25(OH)2D3 prevents the reduction of S1P1expression promoted by Ab(142) and thereby it modulates the downstream signaling leading to ERstress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronictreatment with 1,25(OH)2D3 protects from aggregated Ab(142)-induced damage in the CA1 region ofthe 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)2D3 and its structuralanalogue ZK191784 in counteracting the Ab(142) peptide-induced toxicity through the modulation ofS1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
