Mariarosa Anna Beatrice Melone1, Clemente Dato1, Simona Paladino2, Cinzia Coppola1, Claudia Trebini3, Maria Teresa Giordana3, Lorena Perrone4,5. 1. 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. 2. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80100, Naples, Italy. 3. Department of Neuroscience, University Hospital San Giovanni Battista di Torino, 10126, Molinette, Italy. 4. Universite´Grenoble Alpes, Grenoble, France. perronelorena1@gmail.com. 5. DKFZ, Department of Functional and Structural Genomics, Heidelberg, Germany. perronelorena1@gmail.com.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: The amyloid beta peptide (Aβ1-42) 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 Aβ1-42-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. CONCLUSIONS: 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.
PURPOSE: 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 ADpatients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects. METHODS: 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. RESULTS: The amyloid beta peptide (Aβ1-42) 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 Aβ1-42-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. CONCLUSIONS: 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.
Authors: B D Arbo; C V Marques; I Ruiz-Palmero; A Ortiz-Rodriguez; S Ghorbanpoor; M A Arevalo; L M Garcia-Segura; M F Ribeiro Journal: Brain Res Date: 2015-12-18 Impact factor: 3.252