GLP-1/GIP/Gcg三受体激动剂改善3xTg-AD小鼠认知行为和病理特征研究

Jiao, Juan-Juan and Hölscher, Christian and Li, Tian and Dong, Xue-Fan and Qu, Xue-Song and Cao, Yue and Wu, Mei-Na and Wang, Zhao-Jun and Qi, Jin-Shun (2017) GLP-1/GIP/Gcg三受体激动剂改善3xTg-AD小鼠认知行为和病理特征研究. Acta Physiologica Sinica, 69 (2). pp. 135-145. ISSN 0371-0874

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Abstract

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.

Item Type:
Journal Article
Journal or Publication Title:
Acta Physiologica Sinica
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1314
Subjects:
ID Code:
89144
Deposited By:
Deposited On:
12 Dec 2017 14:46
Refereed?:
Yes
Published?:
Published
Last Modified:
20 Sep 2020 04:31