期刊
BEHAVIOURAL BRAIN RESEARCH
卷 327, 期 -, 页码 65-74出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbr.2017.03.032
关键词
Alzheimer's disease; Incretin; Insulin signaling; Apoptosis; Inflammation; Tau phosphorylation; Type 2 diabetes mellitus
资金
- Shanxi Science and Technology Department under the '100 foreign talents' of the Shanxi province government [2010081062]
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icy. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10 nmol/kg ip.) once-daily for 14 days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y-maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti-apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1(Ser1101) levels and phospho-Akt(ser473) up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. (C) 2017 Elsevier B.V. All rights reserved.
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