基于APP/PS1小鼠皮层和海马蛋白质组的变化探究阿尔茨海默症的潜在机制

doi:10.5246/jcps.2025.05.034

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (5): 443-457.DOI: 10.5246/jcps.2025.05.034

基于APP/PS1小鼠皮层和海马蛋白质组的变化探究阿尔茨海默症的潜在机制

殷宏艳¹^,², 尤斯涵¹^,², 张佳燚³, 孙璐瑶³, 曹津萌³, 刘心星⁴, 李双³^,⁴^,^*(), 郭春燕¹^,²^,^*()

^1. 河北北方学院药学院, 河北张家口 075000
^2. 河北省神经药理学重点实验室, 河北张家口 075000
^3. 河北师范大学生命科学学院, 河北石家庄 050024
^4. 张家口健垣精准医学有限公司, 河北张家口 075000

收稿日期:2024-11-30 修回日期:2024-12-06 接受日期:2025-01-15 出版日期:2025-06-02 发布日期:2025-06-01
通讯作者: 李双, 郭春燕

Proteomic alterations in the cortex and hippocampus of APP/PS1 mice: insights into potential mechanisms of Alzheimer's disease

Hongyan Yin¹^,², Sihan You¹^,², Jiayi Zhang³, Luyao Sun³, Jinmeng Cao³, Xinxing Liu⁴, Shuang Li³^,⁴^,^*(), Chunyan Guo¹^,²^,^*()

¹ Department of Pharmacy, Hebei North University, Zhangjiakou 075000, Hebei, China
² Hebei Key Laboratory of Neuropharmacology, Zhangjiakou 075000, Hebei, China
³ Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-Tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, China
⁴ Jianyuan Precision Medicines (Zhangjiakou) Co., Ltd., Zhangjiakou 075000, Hebei, China

Received:2024-11-30 Revised:2024-12-06 Accepted:2025-01-15 Online:2025-06-02 Published:2025-06-01
Contact: Shuang Li, Chunyan Guo
Supported by:
The S&T Program of Hebei (Grant No. H2021405021), the Project of Hebei North University (Grant No. XJ2023041), and National Level Innovation and Entrepreneurship Project?(Grant No. 202410092005).

摘要/Abstract

摘要：

阿尔茨海默症(Alzheimer’s disease, AD)是导致痴呆的主要原因。尽管有大量诱导阿尔茨海默症的危险因素, 但目前其发病机制仍不明确。本研究目的在于鉴定皮层海马中与AD相关的差异表达蛋白。对比分析表明, APPswe/PSEN1dE9小鼠的空间记忆能力、认知能力和行动能力均受损。通过对大脑皮层组织进行蛋白质组学分析, 鉴定出6405个蛋白质, 其中283个蛋白质被认为是具有统计学意义的差异蛋白; 海马组织共鉴定出5574个蛋白质, 其中244个蛋白质被认为是具有统计学意义的差异蛋白, 所筛选出的蛋白极有可能与AD病理进程有关。生物信息学的功能分析和蛋白质相互作用(PPI)网络图显示, AD在大脑皮层的进程主要由炎症应答相关途径介导, 包括中性粒细胞胞外陷阱的形成、补体和凝血级联。结合PPI分析结果, 发现AD在大脑皮层的进程还与核糖体相关蛋白有关。此外, 还发现一些差异蛋白在大脑皮层和海马中都发生了改变, 包括APP、IDE、SDHB和RB1CC1。这些结果为AD的诊断和治疗提供了新思路。

关键词: 阿尔茨海默病, 蛋白质组学, 皮层, 海马, APPswe/PSEN1dE9

Abstract:

Alzheimer's disease (AD) stands as the principal cause of dementia globally, influenced by myriad risk factors. Despite extensive research, the pathogenesis of AD remains elusive. This study aimed to identify differentially expressed proteins in the cortex and hippocampus that are associated with AD. Our comparative analysis revealed significant impairments in spatial memory, cognitive function, and mobility in APPswe/PSEN1dE9 (APP/PS1) mice. Proteomic analysis of cortex tissues revealed 6405 proteins, with 283 showing significant alterations. In the hippocampus, 5574 proteins were identified, among which 244 were significantly altered, suggesting a connection to AD pathology. Through bioinformatics, functional analysis, and protein-protein interaction (PPI) network mapping, we demonstrated that AD progression in the cortex was predominantly driven by inflammation-related pathways, including neutrophil extracellular trap formation, as well as complement and coagulation cascades. Additionally, PPI analysis linked AD progression in the cortex to ribosome-associated proteins. Moreover, several proteins, including APP, IDE, SDHB, and RB1CC1, exhibited alterations in both the cortex and hippocampus. These findings offered novel insights into the diagnostics and therapeutic strategies for AD.

Key words: Alzheimer's disease, Proteomic, Cortex, Hippocampus, APPswe/PSEN1dE9

Supporting:

殷宏艳, 尤斯涵, 张佳燚, 孙璐瑶, 曹津萌, 刘心星, 李双, 郭春燕. 基于APP/PS1小鼠皮层和海马蛋白质组的变化探究阿尔茨海默症的潜在机制[J]. 中国药学(英文版), 2025, 34(5): 443-457.

Hongyan Yin, Sihan You, Jiayi Zhang, Luyao Sun, Jinmeng Cao, Xinxing Liu, Shuang Li, Chunyan Guo. Proteomic alterations in the cortex and hippocampus of APP/PS1 mice: insights into potential mechanisms of Alzheimer's disease[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(5): 443-457.

图/表 10

Figure 1. Related risk factors of AD.

Figure 2. Workflow of the study.

Figure 3. Comparison of the escape latency in APP/PS1 mice and C57BL/6J mice (n = 10) (A); The number of platform-site crossings of APP/PS1 mice and C57BL/6J mice (B); The dwell time of APP/PS1 mice and C57BL/6J mice (C). ###Denotes P < 0.001 vs. C57BL/6J.

Figure 4. Volcano plot of cortex and limiting by P < 0.05 and FC > 1.5, FC < 0.67, the pink dot and blue dot were indicating that protein both large magnitude of fold-changes (log2 of FC, x-axis) and high statistical significance (–log10 of P-value, y-axis) (A); Volcano plot of hippocampus and limiting by P < 0.05 and FC > 1.5, FC < 0.67, the pink dot and blue dot were indicating that protein both large magnitude of fold-changes (log2 of FC, x-axis) and high statistical significance (–log10 of P-value, y-axis) (B).

Figure 5. Heatmap clustering was visualized for all DEPs of cortex between C57BL/6J and APP/PS1 mice (n = 4) (A); Heatmap clustering was visualized for all expressed significantly proteins of hippocampus between C57BL/6J and APP/PS1 mice (B) (1: C57/BL6J mice; 2: APP/PS1 mice, n = 4).

Figure 6. Top 10 terms of GO analysis of DEPs of cortex (A); Top 10 terms of GO analysis of DEPs of hippocampus (B).

Figure 7. KEGG pathway analysis of DEPs from cortex (A); KEGG pathway analysis of DEPs from hippocampus (B) (P < 0.05).

Figure 8. PPI network of proteins involved in cortex (A) and in hippocampus (B).

Figure 9. The proteins of AD pathway altered both in cortex and hippocampus.

Figure 10. Potential mechanisms of AD progression in the cortex and hippocampus.

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基于APP/PS1小鼠皮层和海马蛋白质组的变化探究阿尔茨海默症的潜在机制

Proteomic alterations in the cortex and hippocampus of APP/PS1 mice: insights into potential mechanisms of Alzheimer's disease

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