Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway

Feng Xiangqian; Wang Donglin; Fu Xiaoyan; Lu Jing; Liu Yating; Yang Hongyan; Gao Yu; Zhou Huadong

doi:10.16016/j.2097-0927.202606040

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Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway

Neuroscience | 更新时间：2026-10-30

- Islet amyloid polypeptide exacerbates cognitive impairment, neuroinflammation, and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway
- Journal of Army Medical University Vol. 48, Issue 20, Pages: 2838-2848(2026)
- 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
  2.陆军军医大学（第三军医大学）大坪医院神经内科，重庆
  3.蚌埠医科大学生命科学研究所，安徽蚌埠
- 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.2097-0927.202606040
  CLC： R341.6;R363.21;R745.7
- Received：09 June 2026，
  
  Revised：2026-09-05，
  
  Accepted：09 September 2026，
  
  Published：30 October 2026
- 稿件说明：
移动端阅览
冯祥谦，王东林，符小艳，等.胰岛淀粉样多肽抑制PI3K/Akt通路而加重阿尔茨海默病小鼠认知损伤、神经炎症及海马Aβ斑块沉积［J］.陆军军医大学学报，2026，48（20）：2838-2848.DOI：10.16016/j.2097-0927.202606040.

Feng X Q，Wang D L，Fu X Y，et al.Islet amyloid polypeptide exacerbates cognitive impairment， neuroinflammation， and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway［J］.J Army Med Univ，2026，48（20）：2838-2848.DOI：10.16016/j.2097-0927.202606040.
冯祥谦，王东林，符小艳，等.胰岛淀粉样多肽抑制PI3K/Akt通路而加重阿尔茨海默病小鼠认知损伤、神经炎症及海马Aβ斑块沉积［J］.陆军军医大学学报，2026，48（20）：2838-2848.DOI：10.16016/j.2097-0927.202606040. DOI：

Feng X Q，Wang D L，Fu X Y，et al.Islet amyloid polypeptide exacerbates cognitive impairment， neuroinflammation， and hippocampal Aβ plaque deposition in Alzheimer’s disease mice by inhibiting the PI3K/Akt pathway［J］.J Army Med Univ，2026，48（20）：2838-2848.DOI：10.16016/j.2097-0927.202606040. DOI：

摘要

目的

胰岛淀粉样多肽（islet amyloid polypeptide，IAPP）是由胰岛β细胞合成分泌的活性多肽，糖尿病时在胰岛形成淀粉样斑块。本研究探讨了IAPP对阿尔茨海默病（Alzheimer’s disease，AD）小鼠认知功能障碍和神经炎性反应等病理损伤的作用。

方法

选用6月龄雌性C57BL/6J野生型（wild type，WT）及APP/PS1转基因AD小鼠，初始体质量20~23 g，按随机数字表法分为（

=5）：WT组（等体积PBS腹腔注射）、WT+IAPP组（200 μg/kg IAPP腹腔注射）、AD组（等体积PBS腹腔注射）、AD+IAPP组（200 μg/kg IAPP腹腔注射），每日给药1次，连续干预10周。Morris水迷宫实验评估小鼠的认知功能；免疫组化检测小鼠海马Aβ斑块数量及面积；透射电镜观察小鼠海马神经元超微结构；生化试剂盒检测小鼠海马组织氧化应激指标H₂O₂水平、超氧化物歧化酶（superoxide dismutase，SOD）和谷胱甘肽过氧化物酶（glutathione peroxidase，GSH-Px）活性；ELISA检测促炎因子IL-1β、IL-6、TNF-α水平以及血清β淀粉样蛋白42（amyloid β-protein 42， Aβ

）水平。基因芯片检测筛选差异表达mRNA，开展GO和KEGG分析，RT-qPCR验证差异mRNA的表达水平。Western blotting检测小鼠海马PI3K/Akt蛋白的相对表达水平。

结果

Morris水迷宫实验结果显示，与WT+IAPP组相比，WT组小鼠学习记忆能力无显著性差异；AD组比WT组小鼠学习记忆能力显著下降（

0.05），AD+IAPP组比AD组小鼠学习记忆能力显著下降（

0.05）。免疫组化提示，与WT组相比，WT+IAPP组小鼠海马的Aβ斑块数量与面积无显著性差异，AD组小鼠海马的Aβ斑块数量与面积明显增加（

0.01）；AD+IAPP组比AD组小鼠的Aβ斑块数量与面积显著增加（

0.01）。透射电镜结果显示，AD+IAPP组比AD组小鼠海马神经元线粒体损伤加重，突触数量明显减少（

0.05）。AD+IAPP组比AD组小鼠海马H

水平显著升高，SOD、GSH-Px活性显著降低（

0.05）。AD+IAPP组比AD组小鼠海马IL-1β、IL-6、TNF-α水平明显上升，血清Aβ

水平明显下降（

0.05）。基因芯片筛选出555个差异mRNA（236个上调、319个下调）；RT-qPCR验证结果与芯片结果一致；GO分析提示差异基因参与跨膜信号传导、神经发育过程；KEGG分析显示差异基因集中于PI3K/Akt通路。Western blotting显示，AD+IAPP组比AD组小鼠海马神经元PI3K和Akt蛋白及p-PI3K和p-Akt蛋白的表达明显降低（

0.05）。

结论

IAPP可以加重AD小鼠的认知功能障碍，增加脑组织神经炎性反应水平，增加海马Aβ斑块沉积，其作用机制可能与抑制PI3K/Akt信号通路的活性有关。

Abstract

Objective

Islet amyloid polypeptide (IAPP) is an active peptide synthesized and secreted by pancreatic β-cells

which forms amyloid plaques in the islets under diabetic conditions. This study aims to determine the effect of IAPP on cognitive impairment

neuroinflammatory response

and other pathological injuries in Alzheimer’s disease (AD) mice.

Methods

Six-month-old female C57BL/6J wild-type (WT) and APP/PS1 transgenic AD mice

with an initial body weight of 20 to 23 g

were randomly divided into 4 groups (

=5): WT group (intraperitoneal injection of equal volume of PBS)

WT+IAPP group (intraperitoneal injection of 200 μg/kg IAPP)

AD group (intraperitoneal injection of equal volume of PBS)

and AD+IAPP group (intraperitoneal injection of 200 μg/kg IAPP). Intraperitoneal injection of IAPP was given to the corresponding mice for 10 consecutive weeks. Morris water maze test was performed to evaluate cognitive function. Immunohistochemistry was applied to detect the number and area of Aβ plaques in the hippocampus. Transmission electron microscopy (TEM) was used to observe the ultrastructural changes in hippocampal neurons. Biochemical kits were employed to detect the levels of hydrogen peroxide (H

) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampal tissues. ELISA was utilized to measure the levels of pro-inflammatory cytokines

including IL-1β

IL-6 and TNF-α

as well as serum amyloid β-protein 42 (Aβ

) concentration. Microarray analysis was conducted to screen differentially expressed mRNAs

followed by GO and KEGG enrichment analyses. RT-qPCR was performed to measure the expression of differential mRNAs. Western blotting was carried out to detect the relative expression levels of proteins related to the PI3K/Akt signaling pathway in hippocampal tissues.

Results

Morris water maze test demonstrated that the learning and memory abilities were no statistical difference between the WT+IAPP group and the WT group

significantly decreased in the AD group than the WT group(

0.05)

and obviously decreased in the AD+IAPP group than the AD group (

0.05). Immunohistochemical staining revealed that compared with the WT group

the number and area of hippocampal Aβ plaques in the WT+IAPP group showed no significant difference

while those in the AD group were significantly increased(

0.01); compared with the AD group

the number and area of Aβ plaques in the AD+IAPP group were significantly increased (

0.01). TEM demonstrated aggravated mitochondrial damage and a remarkable reduction in synaptic number in hippocampal neurons of the AD+IAPP group compared with the AD group (

0.05). The level of H₂O₂ in the hippocampus was significantly increased

while the activities of SOD and GSH-Px were significantly decreased in the AD+IAPP group compared with the AD group (

0.05). The hippocampal levels of IL-1β

IL-6 and TNF-α were significantly elevated

whereas serum Aβ

concentration was notably reduced in the AD+IAPP group compared with the AD group (

0.05). A total of 555 differentially expressed mRNAs (236 upregulated and 319 downregulated) were screened out by microarray

and RT-qPCR verification results were consistent with the results of microarray. GO enrichment analysis indicated that these differentially expressed genes were involved in transmembrane signal transduction and neural development. KEGG analysis revealed that the differential genes were enriched in the PI3K/Akt signaling pathway. Western blotting showed that the protein expression levels of PI3K

Akt

p-PI3K

and p-Akt in hippocampal neurons were significantly decreased in the AD+IAPP group compared with the AD group (

0.0

5).

Conclusion

IAPP can aggravate cognitive dysfunction

enhance inflammatory responses

and promote hippocampal Aβ-plaque deposition in AD mice. Its underlying mechanism may be related to the inhibition of PI3K/Akt signaling-pathway activity.

关键词

Keywords

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