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在T2D-AD小鼠模型中,SGLT2和DPP4抑制剂通过不同的机制改善了类似阿尔茨海默病的病理和认知功能

A Young Sim¹, Da Hyun Choi², Jong Youl Kim³

¹Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea; Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

|October 23, 2023

概括

在2型糖尿病和阿尔茨海默氏病小鼠模型中,抗糖尿病药物,-葡萄糖共运输体-2抑制剂 (SGLT2-i) 和二乙酶-4抑制剂 (DPP4-i) 改善了大脑胰岛素敏感性和认知功能. 这些药物减少了阿尔茨海默氏症的病理,并通过不同的机制增强了大脑的胰岛素信号传递.

科学领域:

神经科学是一个神经科学.
内分泌学在内分泌学.
药理学药理学是指药理学的学科.

背景情况:

阿尔茨海默病 (AD) 和2型糖尿病 (T2D) 具有共同的病理特征,特别是胰岛素耐药性,它越来越多地与AD病变产生有关.
大脑对胰岛素的抵抗是阿尔茨海默病发展的关键因素.
现有的抗糖尿病药物,如-葡萄糖携带载体-2 抑制剂 (SGLT2-i) 和二甲酶-4 抑制剂 (DPP4-i),通过提高胰岛素敏感性来显示神经保护的潜力,但它们在T2D-AD的背景下对大脑新陈代谢和胰岛素抵抗的直接影响仍然在很大程度上未被研究.

研究的目的:

研究SGLT2-i (empagliflozin) 和DPP4-i (sitagliptin) 对大脑新陈代谢和胰岛素抵抗的作用,在2型糖尿病的小鼠模型中,该小鼠模型具有类似阿尔茨海默病的病理学.
在T2D-AD小鼠模型中评估SGLT2-i和DPP4-i在改善认知缺陷和AD相关神经病理方面的治疗潜力.

主要方法:

开发一种T2D-AD小鼠模型,使用高脂肪饮食 (HFD) 和链毒素 (STZ) 管理.
用口服SGLT2-i (empagliflozin) 或DPP4-i (sitagliptin) 治疗T2D-AD小鼠7周.
评估行为结果 (学习,记忆,认知功能),体重,血糖水平,以及对大脑胰岛素信号,AD相关蛋白质 (pTau,Aβ) 和其他信号通路的检查.

主要成果:

T2D-AD小鼠表现出高血糖,体重和胰岛素抵抗,以及认知功能受损.
在T2D-AD小鼠中,SGLT2-i和DPP4-i治疗都显著改善了胰岛素敏感性,减轻了体重,显著增强了海马体依赖的学习,记忆和整体认知表现.
使用SGLT2-i和DPP4-i的治疗干预导致高酸化 (pTau) 和粉样β (Aβ) 积累的水平降低,并改善了大脑的胰岛素信号传递. SGLT2-i通过ACE2/Ang-(1-7) /MasR轴来降低pTau,而DPP4-i增加了胰岛素降解酶 (IDE) 来降低Aβ.

结论:

在T2D小鼠模型中,SGLT2-i和DPP4-i在预防AD类病理和认知衰退方面显示出显著的治疗潜力.
这些抗糖尿病药物似乎通过通过不同的分子机制调节大脑胰岛素信号来发挥其神经保护作用.
这些发现表明,用SGLT2-i或DPP4-i针对大脑胰岛素耐药性可能是管理并发性T2D和AD的可行策略.

关键词:

阿尔茨海默氏症是阿尔茨海默氏症的一种疾病.粉样蛋白β 粉样蛋白β 这是一种二乙-4抑制剂.过酸化的酸.糖共运输体-2 抑制剂 2型糖尿病是什么? 2型糖尿病是什么

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