Involvement of insulin signalling pathway in methamphetamine-induced hyperphosphorylation of Tau.

Abstract

Methamphetamine (METH), an amphetamine-like drug, is one of the most commonly used central nervous system psychostimulants worldwide. METH abuse frequently leads to cognitive decline and dementia-like changes, but the mechanisms remain poorly understood. In the present study, the mechanisms of METH-induced changes in Alzheimer's disease-like pathological protein in Neuro2A cells were explored. Our results indicated that METH exposure significantly increased the expression of the pathological protein hyperphosphorylated tau (p-tau). Further analysis revealed that METH exposure obviously disrupted insulin signalling, resulted in brain insulin resistance, which manifested as downregulation of the insulin receptor substrate-1, AKTser 473, and GSK3β activation. Notably, the linkage between p-tau expression and insulin signalling can be partially verified by treatment with the insulin-sensitizing drug rosiglitazone and GSK3β inhibitor TWS119 which specifically reversed METH-induced hyperphosphorylation of tau. Our results indicate that insulin signalling can be therapeutically exploited for attenuating METH-induced upregulation of p-tau.

• Authors: Huaisha Xu, Xiaodong Chen, Jun Wang, Tingyu Yang, Na Liu, Jie Cheng, Rong Gao, Jingli Liu, Hang Xiao
• Journal: Toxicology (Toxicology) Vol. 408 Pg. 88-94 (09 01 2018) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 29981415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Central Nervous System Stimulants
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Mapt protein, mouse
• tau Proteins
• Methamphetamine
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Line, Tumor
• Central Nervous System Stimulants (toxicity)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Insulin (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Methamphetamine (toxicity)
• Mice
• Neurons (drug effects, metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Up-Regulation
• tau Proteins (metabolism)