Pramlintide improves cognitive function in Alzheimer’s disease mice through antioxidant stress and PI3K/Akt pathway

LIU Yating; LU Jing; FENG Xiangqian; WANG Dongling; LIAO Qirong; YANG Hongyan; ZHOU Huadong

doi:10.16016/j.2097-0927.202505072

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Pramlintide improves cognitive function in Alzheimer’s disease mice through antioxidant stress and PI3K/Akt pathway

Monographic Reports | 更新时间：2025-08-25

- Pramlintide improves cognitive function in Alzheimer’s disease mice through antioxidant stress and PI3K/Akt pathway
- Journal of Army Medical University Vol. 47, Issue 16, Pages: 1862-1871(2025)
- 作者机构：
  
  1.蚌埠医科大学第一附属医院神经内科，安徽蚌埠
  2.陆军特色医学中心（第三军医大学大坪医院）神经内科，重庆
- 作者简介：
  
  ZHOU Huadong， E-mail： zhouhuad@163.com
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81771177)
- DOI：10.16016/j.2097-0927.202505072
  CLC： R338.64;R745.7;R977.6
- Received：29 May 2025，
  
  Revised：24 July 2025，
  
  Published：30 August 2025
- 稿件说明：
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刘雅婷,卢静,冯祥谦,等.普兰林肽通过抗氧化应激和PI3K/Akt通路改善阿尔茨海默病小鼠认知功能[J].陆军军医大学学报,2025,47(16):1862-1871.

LIU Yating,LU Jing,FENG Xiangqian,et al.Pramlintide improves cognitive function in Alzheimer’s disease mice through antioxidant stress and PI3K/Akt pathway[J].J Army Med Univ,2025,47(16):1862-1871.
刘雅婷,卢静,冯祥谦,等.普兰林肽通过抗氧化应激和PI3K/Akt通路改善阿尔茨海默病小鼠认知功能[J].陆军军医大学学报,2025,47(16):1862-1871. DOI：10.16016/j.2097-0927.202505072.

LIU Yating,LU Jing,FENG Xiangqian,et al.Pramlintide improves cognitive function in Alzheimer’s disease mice through antioxidant stress and PI3K/Akt pathway[J].J Army Med Univ,2025,47(16):1862-1871. DOI：10.16016/j.2097-0927.202505072.

摘要

目的

探讨胰淀粉样多肽类似物普兰林肽（Pramlintide）通过抗氧化应激机制对阿尔茨海默病小鼠学习记忆的影响，并检测磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路的表达。

方法

动物实验将APP/PS1小鼠分为2组（每组5只）：阿尔茨海默病组（AD组）和普兰林肽治疗组（AD+Pramlintide组）；普兰林肽组每日经腹腔注射0.5 μmol/L，AD组小鼠腹腔注射相同剂量的PBS；腹腔注射时间为10周。采用水迷宫检测学习记忆能力，HE染色和免疫组化技术观察脑海马组织病理形态变化，高尔基染色观察海马组织树突棘的形态特征，透射电镜（TEM）观察海马神经元超微结构；生化方法检测小鼠海马组织丙二醛（MDA）含量和超氧化物歧化酶（SOD）水平，酶联免疫吸附实验（ELISA）试剂盒定量分析检测炎症因子白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平；Western blot技术检测海马组织中PI3K/Akt信号通路相关蛋白的表达。细胞实验采用SH-SY5Y细胞加入Aβ1-42建立AD细胞模型，用普兰林肽处理细胞后，检测氧化应激和炎性反应水平，免疫荧光检测细胞凋亡。

结果

动物实验表明，与不加普兰林肽处理相比，普兰林肽处理的小鼠平台潜伏期明显缩短（

0.01），穿越平台次数显著增多（

0.01），探索隐藏平台时间延长（

0.01）。普兰林肽处理的小鼠HE染色显示海马组织神经元密度高，排列较整齐（

0.05），免疫组化结果显示Aβ蛋白明显降低（

0.01），高尔基染色结果显示树突棘数量增加（

0.05），透射电镜结果显示神经元线粒体结构较为完整、空泡化明显减少，形态特征清晰可辨。与不加普兰林肽处理相比，治疗组的氧化应激和炎性反应水平降低（

0.01），WB结果显示p-PI3K/PI3K、p-Akt/Akt蛋白相对表达升高（

0.01）。细胞实验表明，用普兰林肽处理的AD细胞模型氧化应激和炎性反应水平降低（

0.01），免疫荧光结果显示细胞凋亡降低（

0.01）。

结论

普兰林肽能够改善AD小鼠的认知功能，减少海马组织Aβ沉积，降低氧化应激和炎性反应，减轻了神经元超微结构的病理改变，同时增强了PI3K/Akt信号通路的表达。

Abstract

Objective‍　‍To investigate the effect of pramlintide

a pancreatic amyloid peptide analog

on learning and memory of Alzheimer’s disease (AD) mice through antioxidant stress

and to determine the expression of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Methods‍　‍The APP/PS1 mice were divided into a pramlintide treatment group (intraperitoneal injection of 0.5 μmol/L per day for 10 weeks) and an AD group (same dose of PBS)

with 5 mice in each group. The learning and memory abilities were detected with water maze test

the pathological changes of the hippocampus were observed with HE staining and immunohistochemistry

the morphological characteristics of dendritic spines in hippocampus were observed after Golgi staining

and the ultrastructure of hippocampal neurons was observed through transmission electron microscopy (TEM). The content of malondialdehyde (MDA) and the level of superoxide dismutase (SOD) in the hippocampal tissue were detected by biochemical assay

and the levels of inf

lammatory factors IL-6

TNF-α and IL-1β were determined with ELISA. Western blotting was applied to measure the expression of PI3K/Akt signaling pathway related proteins in the hippocampus. In the cell experiment

SH-SY5Y cells were added with Aβ 1-42 to establish a cell model of AD. After the cells were treated with pramlintide

the levels of oxidative stress and inflammatory response were detected

and cell apoptosis was detected by immunofluorescence. Results‍　‍The animal experiments showed that pramlintide treatment resulted in significantly shortened escape latency (

0.01)

increased platform crossings (

0.01)

and prolonged time to exploring hidden platform (

0.01). In the hippocampal tissue of the pramlintide treatment group

HE staining displayed hippocampal neurons in high density and neat arrangement (

0.05)

immunohistochemical results showed significantly reduced Aβ protein (

0.01)

Golgi staining results demonstrated more dendritic spines (

0.05)

TEM revealed almost intact neuronal mitochondrial structure

with reduced vacuolization and clear and identifiable morphology. When compared with the AD group

the levels of oxidative stress and inflammatory response were decreased (

0.01)

and the relative expression of p-PI3K/PI3K and p-Akt/Akt proteins was increased (

0.01) in the treatment group. In cell experiments

the levels of oxidative stress and inflammatory response were decreased in AD cell model after pramlintide treatment (

0.01)

and the results of immunofluorescence showed that cell apoptosis was declined (

0.01). Conclusion‍　‍Pramlintide can improve the cognitive function

reduce the hippocampal deposition of Aβ

reduce oxidative stress and inflammatory response

alleviate the pathological changes of neuronal ultrastructure

and enhance the expression of PI3K/Akt signaling pathway in

AD mice.

关键词

Keywords

references

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