NEUROBIOLOGY OF AGING | 卷:57 |
Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes | |
Article | |
Dey, Aditi1  Hao, Shuai1  Wosiski-Kuhn, Marlena1,2  Stranahan, Alexis M.1  | |
[1] Augusta Univ, Dept Neurosci & Regenerat Med, Augusta, GA USA | |
[2] Wake Forest Univ, Dept Neurobiol & Anat, Sch Med, Winston Salem, NC 27157 USA | |
关键词: Insulin resistance; Diabetes; Hippocampus; Tau phosphorylation; Learning and memory; Corticosterone; | |
DOI : 10.1016/j.neurobiolaging.2017.05.010 | |
来源: Elsevier | |
【 摘 要 】
Type 2 diabetes is increasingly recognized as a risk factor for Alzheimer's disease, but the underlying mechanisms remain poorly understood. Hyperphosphorylation of the microtubule-associated protein tau has been reported in rodent models of diabetes, including db/db mice, which exhibit insulin resistance and chronically elevated glucocorticoids due to leptin receptor insufficiency. In this report, we investigated endocrine mechanisms for hippocampal tau phosphorylation in db/db and wild-type mice. By separately manipulating peripheral and intrahippocampal corticosterone levels, we determined that hippocampal corticosteroid exposure promotes tau phosphorylation and activates glycogen synthase kinase 3 beta (GSK3 beta). Subsequent experiments in hippocampal slice preparations revealed evidence for a nongenomic interaction between glucocorticoids and GSK3 beta. To examine whether GSK3 beta activation mediates tau phosphorylation and impairs memory in diabetes, db/db and wild-type mice received intrahippocampal infusions of TDZD-8, a non-ATP competitive thiadiazolidinone inhibitor of GSK3 beta. Intrahippocampal TDZD-8 blocked tau hyperphosphorylationand normalized hippocampus-dependent memory in db/db mice, suggesting that pathological synergy between diabetes and Alzheimer's disease may involve glucocorticoid-mediated activation of GSK3 beta. (C) 2017 Elsevier Inc. All rights reserved.
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