Vitamin D 3 protects against Aβ peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis

Abstract

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.

Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation

“…Vitamin D and its analogues were incubated in a final concentration of 100 nM. The concentration that was used corresponds to physiological serum concentrations of approximately 75 nmol/L [ 47 , 48 ], and is frequently used for cell culture experiments [ 26 , 49 , 50 ]. Furthermore, no significant change in cell viability was found using 100 nM vitamin D as compared to the solvent control ( supplement Figure S1 ).…”

“…In line with our results, a similar reduction of approximately 50% in Aβ 40 and Aβ 42 peptides and a decrease in the number of amyloid plaques has also been shown in APP transgenic mice that were fed for five months with a vitamin D enriched diet [ 70 ]. Beside the potential of vitamin D to reduce Aβ level it has been recently shown that vitamin D 3 protects against Aβ peptide cytotoxicity by reverting the Aβ 1–42 induced reduction in the sphingosine-1-phosphate/ceramide ratio [ 26 ]. We found that vitamin D 3 and analogues of vitamin D 3 and D 2 reduce secreted Aβ peptide level by decreasing amyloidogenic APP processing and by an elevation of Aβ-degradation.…”

“…Total Aβ level is not only dependent on the proteolytic activities of the APP cleaving secretases, but also on Aβ-degradation, involving e.g., the Aβ degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) [ 13 , 14 ]. In addition to several lipids that influence the generation, degradation, and aggregation of Aβ peptides [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], it has recently been shown that fat soluble vitamins affect molecular mechanisms that are involved in AD pathogenesis, e.g., Aβ-induced neurotoxicity, oxidative stress, inflammatory processes, as well as Aβ-generation, Aβ-degradation, and Aβ-clearance [ 26 , 27 , 28 , 29 , 30 , 31 ]. Several vitamins, including vitamin A, provitamin Aβ-carotene, vitamin D 3 , vitamin K, and vitamin E, have also been reported to be reduced in plasma/serum of AD patients [ 30 , 32 , 33 , 34 , 35 , 36 ] and vitamin D hypovitaminosis affects up to 90% of the elderly population [ 37 ].…”

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

“…In addition, p38 MAPK activation upregulated its direct downstream target, c -Jun, known as an apoptotic transcription factor that can cause neuronal cell death in AD [ 84 ]. In vitro studies using primary cultured neurons and immortalized neuronal cells have shown that exposure to Aβ in these cells activates p38 MAPK and contributes to neuronal apoptosis [ 85 , 86 , 87 , 88 ]. These results were further confirmed in various AD animal models [ 89 , 90 , 91 , 92 , 93 ].…”

Crosstalk between sphingolipids and vitamin D3: potential role in the nervous system

“…Preliminary results in our laboratory indicate that the crosstalk between SLs and 1,25(OH) 2 D 3 leads to a specific balance between neurodegeneration/neuroprotection in neuronal cells. In particular, in human SH‐SY5Y differentiated cells, we found that 1,25(OH) 2 D 3 treatment counteracts the down‐regulation of S1P1‐mediated signalling promoted by Aβ1–42 (Pierucci et al ., ).…”