Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, Second Division of Neurology, Center for Rare Neurological e Neuromuscular Diseases and Interuniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, 80100, Naples, Italy.
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80100, Naples, Italy.
Pharm Res. 2018 Feb 5;35(2):44. doi: 10.1007/s11095-017-2276-2.
Oxidative stress is a hallmark of Alzheimer's Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects.
We analyzed TXNIP expression and tau phosphorylation in the hippocampus of the 5xFAD mice in the absence and presence of a pharmacological treatment with Verapamil. Using SH-SY5Y cells, we verified the causative role of TXNIP in promoting tau phosphorylation at Ser202/Thr205, by inducing TXNIP silencing.
The amyloid beta peptide (Aβ) leads to TXNIP over-expression in SH-SY5Y cells, which in turns induces oxidative stress and the activation of p38 MAPK, promoting tau phosphorylation at Ser202/Thr205. Silencing of TXNIP abolishes Aβ-induced tau phosphorylation, p38 MAPK phosphorylation and subsequent tau phosphorylation. Verapamil prevents TXNIP expression as well as p38 MAPK and tau phosphorylation at Ser202/Thr205 in the hippocampus of the 5xFAD mice.
Our study unveil a novel pathway involved in AD progression that is inhibited by Verapamil, shedding new light on the understanding of the therapeutic potential of Verapamil in AD.
氧化应激是阿尔茨海默病（AD）的标志，并促进tau 磷酸化。由于 Thioredoxin 相互作用蛋白（TXNIP）是 Thioredoxin 抗氧化系统的抑制剂，在 AD 患者的海马体中上调，我们研究了 TXNIP 是否在促进 tau 磷酸化中起作用，以及维拉帕米（TXNIP 表达的抑制剂）是否可以预防 TXNIP 的下游效应。
我们分析了 5xFAD 小鼠海马体中 TXNIP 表达和 tau 磷酸化的情况，以及维拉帕米的药理学处理是否存在。通过诱导 TXNIP 沉默，我们在 SH-SY5Y 细胞中验证了 TXNIP 在促进 tau 磷酸化 Ser202/Thr205 中起因果作用。
淀粉样β肽（Aβ）导致 SH-SY5Y 细胞中 TXNIP 的过表达，继而诱导氧化应激和 p38 MAPK 的激活，促进 tau 磷酸化 Ser202/Thr205。TXNIP 沉默可消除 Aβ诱导的 tau 磷酸化、p38 MAPK 磷酸化和随后的 tau 磷酸化。维拉帕米可防止 5xFAD 小鼠海马体中 TXNIP 表达以及 p38 MAPK 和 tau 磷酸化 Ser202/Thr205。
我们的研究揭示了 AD 进展中涉及的新途径，该途径可被维拉帕米抑制，为理解维拉帕米在 AD 中的治疗潜力提供了新的认识。
