Abstract：
Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer\'s disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-β (Aβ), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aβ, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.
摘要：
Tirzepatide(LY3298176),GLP-1和GIP受体激动剂，是脂肪酸修饰和39个氨基酸的线性肽，改善糖尿病大鼠学习记忆障碍。然而,具体的分子机制仍然未知。在本研究中,我们研究了替利西帕肽在阿尔茨海默病（AD）模型小鼠中的神经保护作用。Tirzepatide腹膜内（i.p.）给予APP/PS1小鼠8周，每周一次，剂量为10nmol/kg，它显著降低了GLP-1R的水平，皮质中GFAP蛋白表达和淀粉样斑块，它还降低了淀粉样蛋白β（Aβ）诱导的神经元凋亡，但不影响APP/PS1小鼠的焦虑和认知功能。此外，替瑞哌肽降低血糖水平，增加GLP-1R的mRNA表达，SACF1,ATF4,Glu2A,APP/PS1小鼠下丘脑中的Glu2B。Tirzepatide增加葡萄糖转运蛋白1，己糖激酶的mRNA表达，葡萄糖-6-磷酸脱氢酶,和皮质中的磷酸果糖激酶。最后,tirzepatide通过调节Aβ引起的活性氧的产生和线粒体膜电位来改善能量代谢，从而通过GLP-1R降低星形胶质细胞中的线粒体功能和ATP水平。这些结果提供了有价值的见解大脑葡萄糖代谢和线粒体功能的机制替利哌肽,提出了AD治疗的潜在策略。
