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P3‐039: GWAS LOAD LOCI SIGNALING NETWORKS SHARE SIMILARITIES WITH TG2576 MOUSE HIPPOCAMPAL NETWORKS AFFECTED DURING COGNITIVE ENHANCEMENT BY PPARγ AGONISM WITH ROSIGLITAZONE
Author(s) -
Dineley Kelly,
Denner Larry,
Jahrling Jordan,
Urban Travis
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.1126
Subject(s) - genome wide association study , biology , rosiglitazone , creb , genetic association , computational biology , transcriptome , gene , genetics , interactome , gene regulatory network , neuroscience , gene expression , receptor , single nucleotide polymorphism , transcription factor , genotype
utilization and deficient energy metabolism occur in AD suggests a role for impaired insulin signaling in the pathogenesis of it. Increased levels of tauproteinare elevated in AD brain, and NFTs composed of hyperphosphorylated tau is a neuropathological feature of AD. Studies suggest that tau is correlated with insulin pathway, however whether the increased tau in AD induces insulin resistance still remain elusive. Methods: To address this question, mouse neuroblastoma Neuro2a (N2a) cells were transfected with human full-length tau or tau siRNA before treated with 100nM insulin. Thereafter, the activity of insulin signaling pathway and related kinases were analyzed in different time points (0, 1, 5, 10, 30, 60 min). Results: We found that N2a cells overexpressing tau were more resistant to the insulin stimulation than wild type cells. The insulin pathway including insulin receptor, PDK and Akt was less activated by insulin in both time course and amplitude when tau was overexpressed. In addition, the activation of downstream of insulin pathway including mTOR, p70S6K and GSK-3b under insulin stimulating was also attenuated in the N2a cells overexpressing tau. These effects of tau on insulin pathway were confirmed by using tau siRNA. The mechanism underlying tau-induced insulin resistance was mediated by the impaired phosphorylation of insulin receptor substrate (IRS). We demonstrated that elevated tau increased the activity of JNK, which can phosphorylate IRS at the serine site. Phosphorylated serine site of IRS will inhibit the tyrosine site being phosphorylated by insulin, which may lead to insulin resistance. Conclusions: These findings suggest that the intracellular kinases such as JNK may be implicated in the disturbed insulin signaling cascade through which overexpressed tau induces insulin resistance and further supports the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.