Association between cognitive impairment and hippocampal proteomic alterations in an APP/PS1 mouse model of Alzheimer’s disease

Yi Zhenzhen; Dai Jialin; An Xiaoqiong; Wang Jian; Xiong Ling; Fan Zhonghao; Wang Jiawen

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Association between cognitive impairment and hippocampal proteomic alterations in an APP/PS1 mouse model of Alzheimer’s disease

更新时间：2026-07-01

- Association between cognitive impairment and hippocampal proteomic alterations in an APP/PS1 mouse model of Alzheimer’s disease
- Journal of Chongqing Medical University Pages: 1-12(2026)
- 作者机构：
  
  1.贵州医科大学法医学院，贵阳 550004
  2.赣南医科大学基础医学院，赣州 341000
  3.贵州医科大学基础医学院，贵安 561113
- 作者简介：
- 基金信息：
- DOI：
  CLC： R749.16
- Received：24 February 2026，
  
  Revised：2026-05-20，
  
  Accepted：20 May 2026，
  
  Published：01 July 2026
- 稿件说明：
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Yi Zhenzhen,Dai Jialin,An Xiaoqiong,et al.Association between cognitive impairment and hippocampal proteomic alterations in an APP/PS1 mouse model of Alzheimer’s disease[J].Journal of Chongqing Medical University,
DOI：

Yi Zhenzhen,Dai Jialin,An Xiaoqiong,et al.Association between cognitive impairment and hippocampal proteomic alterations in an APP/PS1 mouse model of Alzheimer’s disease[J].Journal of Chongqing Medical University, DOI：10.13406/j.cnki.cyxb..

摘要

目的

阿尔茨海默病（Alzheimer’s disease，AD）是一种以进行性认知功能衰退为特征的神经退行性疾病，其发病机制主要包括β淀粉样蛋白（amyloid β-protein，Aβ）沉积、神经炎症和突触功能障碍等多种病理过程。本研究旨在通过整合蛋白质组学和行为学分析，揭示淀粉样前体蛋白/早老素1（Amyloid Precursor Protein/Presenilin 1，APP/PS1）双转基因的AD小鼠模型中关键分子的变化。

方法

采用4D无标记定量液相色谱-串联质谱（Four-dimensional Label-free Liquid Chromatography-Tandem Mass Spectrometry，4D Label-free LC-MS/MS）技术对6月龄APP/PS1小鼠海马组织进行蛋白质组学分析，结合Morris水迷宫行为学评估（结果显示该模型存在显著空间记忆障碍）和生物信息学方法。

结果

共鉴定出5803个蛋白质，其中73个差异表达蛋白（39个上调和34个下调）。功能富集分析表明这些蛋白显著参与神经系统发育、免疫反应、溶酶体通路和Notch信号通路等与AD相关的生物学过程。关键蛋白对应基因分析发现，与神经炎症和凋亡相关的基因表达上调，如组织蛋白酶S（Cathepsin S，Ctss）、补体C1q B链（complement C1q B chain，C1qb）、棕榈酰蛋白硫酯酶1（palmitoyl-protein thioesterase 1，Ppt1）等基因；而神经保护因子等下调，如核受体亚家族3C组成员1（nuclear receptor subfamily 3 group C member 1，Nr3c1）、CDK5调控亚基相关蛋白3（CDK5 regulatory subunit associated protein 3，Cdk5rap3）等基因。蛋白质印迹（Western blot，WB）验证结果与质谱数据一致。染色体定位分析进一步揭示了这些基因的基因组分布特征，提示其可能存在协同调控机制。

结论

本研究系统揭示了APP/PS1小鼠海马区的蛋白质组特征，发现溶酶体功能障碍和补体系统激活可能促进AD相关病理过程。上述结果不仅为AD的早期诊断提供了潜在生物标志物（如Ctss和C1qb），也为靶向神经炎症和蛋白质代谢紊乱的多靶点治疗策略的制定奠定了理论基础。

Abstract

Objective

Alzheimer’s disease（AD） is a neurodegenerative disease characterized by progressive cognitive decline，and its pathogenesis involves various pathological processes such as β-amyloid（Aβ） deposition，neuroinflammation，and synaptic dysfunction. This study aims to investigate key molecular changes in an APP/PS1 transgenic mouse model of AD by integrating proteomic and behavioral analyses.

Methods

The 4D Label-free LC-MS/MS technique was used to perform a proteomic analysis on the hippocampal tissue of APP/PS1 mice aged 6 months，and the Morris water maze test was used for behavioral assessment （the results showed significant spatial memory impairment in this model）. Bioinformatics methods were also applied.

Results

A total of 5803 proteins were identified，including 73 differentially expressed proteins（39 upregulated proteins and 34 downregulated proteins）. The functional enrichment analysis showed that these proteins were significantly involved in AD-related biological processes such as nervous system development，immune response，lysosomal pathway，and the Notch signaling pathway. The key gene analysis showed that the genes related to neuroinflammation and apoptosis（such as Ctss，C1qb，and Ppt1） were upregulated，while neuroprotective factors（such as Nr3c1 and Cdk5rap3） were downregulated. The results of Western blot validation were consistent with mass spectrometry data. The chromosomal localization analysis further revealed the genomic distribution characteristics of these genes，suggesting the presence of potential co-regulatory mechanisms.

Conclusion

This study systematically reports the proteomic characteristics of the hippocampal region in APP/PS1 mice，and the results show that lysosomal dysfunction and complement system activation may be involved in AD-related pathological processes. The above results not only provide potential biomarkers （such as Ctss and C1qb） for the early diagnosis of AD，but also lay a theoretical foundation for the development of multi-target therapeutic strategies for neuroinflammation and protein metabolic disorders.

关键词

Keywords

references

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