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A GLP-1/GIP/Gcg receptor triagonist improves memory behavior, as well as synaptic transmission, neuronal excitability and Ca2+ homeostasis in 3xTg-AD mice.
Neuropharmacology ( IF 4.6 ) Pub Date : 2020-03-06 , DOI: 10.1016/j.neuropharm.2020.108042
Tian Li 1 , Juan-Juan Jiao 2 , Qiang Su 1 , Christian Hölscher 3 , Jun Zhang 1 , Xu-Dong Yan 1 , Hui-Min Zhao 1 , Hong-Yan Cai 4 , Jin-Shun Qi 1
Affiliation  

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca2+ flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca2+ balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD.

中文翻译:

GLP-1 / GIP / Gcg受体激动剂可改善3xTg-AD小鼠的记忆行为以及突触传递,神经元兴奋性和Ca2 +稳态。

阿尔茨海默氏病(AD)是一种进行性神经退行性疾病,严重影响人类健康,目前的治疗方法无法阻止这种疾病。2型糖尿病(T2DM)是AD的危险因素。我们最近的研究报道了一种新型单分子抗糖尿病药物GLP-1 / GIP /胰高血糖素受体三激动剂(Triagonist)对3xTg-AD小鼠的认知和病理学改善的神经保护作用。但是,神经保护的详细电生理和分子机制仍待探索。本研究通过使用全细胞膜片钳技术进一步研究了潜在的电生理和分子机制。我们的研究结果表明,在放射状迷宫测试中,长期的Triagonist治疗有效降低了3xTg-AD小鼠的工作记忆和参考记忆错误。此外,Triagonist增强了3xTg-AD小鼠海马切片中自发的兴奋性突触活动,电压和化学门控的Ca2 +通量的差异调节,并减少了锥体神经元的过度兴奋。此外,长期的Triagonist治疗还上调了3xTg-AD小鼠海马中突触素和PSD-95的表达水平。这些结果表明,Triagonist可以改善3xTg-AD小鼠的记忆形成以及突触传递,Ca2 +平衡和神经元兴奋性。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新的治疗策略。差分调制的电压和化学门控的Ca2 +通量,并减少了3xTg-AD小鼠海马切片中锥体神经元的过度兴奋。此外,长期的Triagonist治疗还上调了3xTg-AD小鼠海马中突触素和PSD-95的表达水平。这些结果表明,Triagonist可以改善3xTg-AD小鼠的记忆形成以及突触传递,Ca2 +平衡和神经元兴奋性。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新的治疗策略。差分调制的电压和化学门控的Ca2 +通量,并减少了3xTg-AD小鼠海马切片中锥体神经元的过度兴奋。此外,长期的Triagonist治疗还上调了3xTg-AD小鼠海马中突触素和PSD-95的表达水平。这些结果表明,Triagonist可以改善3xTg-AD小鼠的记忆形成以及突触传递,Ca2 +平衡和神经元兴奋性。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新颖的治疗策略。慢性Triagonist治疗还上调了3xTg-AD小鼠海马中突触素和PSD-95的表达水平。这些结果表明,Triagonist可以改善3xTg-AD小鼠的记忆形成以及突触传递,Ca2 +平衡和神经元兴奋性。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新颖治疗策略。慢性Triagonist治疗还上调了3xTg-AD小鼠海马中突触素和PSD-95的表达水平。这些结果表明,Triagonist可以改善3xTg-AD小鼠的记忆形成以及突触传递,Ca2 +平衡和神经元兴奋性。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新颖治疗策略。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新颖治疗策略。Triagonist的这些神经保护作用可能与突触素和PSD-95的上调有关。因此,该研究表明多受体激动剂可能是治疗AD的一种新颖治疗策略。
更新日期:2020-03-06
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