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A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model

•Novel dual GLP-1/GIP receptor agonists are superior to single GLP-1 agonists.•In the icv. STZ model of neurodegeneration, a novel dual agonist was highly effective at low doses.•Cognition was protected, inflammation reduced.•Insulin signaling was re-sensitized, apoptotic signaling reduced. Alzheime...

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Bibliographic Details
Published in:Behavioural brain research 2017-06, Vol.327, p.65-74
Main Authors: Shi, Lijuan, Zhang, Zhihua, Li, Lin, Hölscher, Christian
Format: Article
Language:English
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Summary:•Novel dual GLP-1/GIP receptor agonists are superior to single GLP-1 agonists.•In the icv. STZ model of neurodegeneration, a novel dual agonist was highly effective at low doses.•Cognition was protected, inflammation reduced.•Insulin signaling was re-sensitized, apoptotic signaling reduced. 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 icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days 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-IRS1Ser1101 levels and phospho-AktSer473 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.
ISSN:0166-4328
1872-7549
DOI:10.1016/j.bbr.2017.03.032