胰淀素对阿尔茨海默病小鼠脑组织中circRNA和mRNA表达谱的影响

侯明亮; 马琳秋; 李金平; 李小雄; 马晶晶; 黄洁; 廖旗荣; 杨红岩; 周华东

doi:10.16016/j.2097-0927.202304089

您当前的位置：

首页 >

文章列表页 >

胰淀素对阿尔茨海默病小鼠脑组织中circRNA和mRNA表达谱的影响

基础医学 | 更新时间：2026-01-09

- 胰淀素对阿尔茨海默病小鼠脑组织中circRNA和mRNA表达谱的影响
- Effect of amylin on expression profiles of circRNAs and mRNAs in brain tissue of Alzheimer's disease mice
- 陆军军医大学学报 2023年45卷第19期页码：2018-2028
- 作者机构：
  
  1.233004 安徽蚌埠，蚌埠医学院第一附属医院神经内科
  2.400042 重庆，陆军特色医学中心神经内科
- 作者简介：
  
  [周华东，E-mail：zhouhuad@163.comZHOU Huadong, E-mail: zhouhuad@163.com
- 基金信息：
  
  ‍基‍金‍项‍目‍］‍ ‍国家自然科学基金面上项目(81771177);利益冲突声明所有作者声明不存在利益冲突;作者贡献声明侯明亮：实验操作、论文撰写；马琳秋、李金平、黄洁、廖旗荣、杨红岩：数据整理；李小雄、马琳秋：统计学分析；周华东：研究指导、论文修改、经费支持
- DOI：10.16016/j.2097-0927.202304089
  中图分类号： R745.7;R966;R977.6
- 收稿：2023-04-21，
  
  修回：2023-05-17，
  
  纸质出版：2023-10-15
- 稿件说明：
移动端阅览
侯明亮, 马琳秋, 李金平, 等. 胰淀素对阿尔茨海默病小鼠脑组织中circRNA和mRNA表达谱的影响[J]. 陆军军医大学学报, 2023,45(19):2018-2028.

Mingliang HOU, Linqiu MA, Jinping LI, et al. Effect of amylin on expression profiles of circRNAs and mRNAs in brain tissue of Alzheimer's disease mice[J]. Journal of Army Medical University, 2023, 45(19): 2018-2028.
侯明亮, 马琳秋, 李金平, 等. 胰淀素对阿尔茨海默病小鼠脑组织中circRNA和mRNA表达谱的影响[J]. 陆军军医大学学报, 2023,45(19):2018-2028. DOI： 10.16016/j.2097-0927.202304089.

Mingliang HOU, Linqiu MA, Jinping LI, et al. Effect of amylin on expression profiles of circRNAs and mRNAs in brain tissue of Alzheimer's disease mice[J]. Journal of Army Medical University, 2023, 45(19): 2018-2028. DOI： 10.16016/j.2097-0927.202304089.

摘要

目的

研究胰淀素(islet amyloid polypeptide

IAPP)腹腔注射对阿尔茨海默病(Alzheimer’s disease

AD)小鼠和野生型(wild-type，WT)小鼠脑组织中环状RNA(circular RNA

circRNA)和信使RNA(messenger RNA

mRNA)表达谱的影响。

方法

选取10月龄20~30 g雄性APP/PS1转基因AD模型小鼠和C57 WT小鼠各6只，把6只AD小鼠和WT小鼠使用随机数字表法分成2组，每组3只。腹腔注射IAPP的AD小鼠(AD

+IAPP

)作为实验组，腹腔注射IAPP的WT小鼠(WT

+IAPP

)作为对照组，腹腔注射相同剂量的磷酸盐缓冲液(PBS)的AD小鼠(AD

+PBS

)和WT小鼠(WT

+PBS

)作为空白对照组。干预结束后，提取4组小鼠脑组织总RNA，进行基因芯片测序，筛选出AD

+IAPP

与WT

+IAPP

相比差异表达的circRNA和mRNA，以及AD

+PBS

与WT

+PBS

相比差异表达的circRNA和mRNA。在AD

+IAPP

与WT

+IAPP

相比筛选出来的差异circRNA中，选取6个差异表达的circRNA，进行实时定量聚合酶链反应(qRT-PCR)验证基因芯片结果的可靠性。对差异表达的mRNA进行基因本体论(gene ontology

GO)富集分析与京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes

KEGG)通路富集分析。随后构建显著差异表达的circRNA_45921的ceRNA(competitive endogenous RNA)网络。

结果

+IAPP

与WT

+IAPP

比较，显著差异表达的circRNA共有237个，其中157个上调，80个下调；显著差异表达mRNA共有663个，其中348个上调，315个下调。qRT-PCR结果显示6个差异表达的circRNA与基因芯片结果一致，基因芯片测序结果可靠。GO富集分析显示差异表达上调的mRNA在核苷磷酸结合、细胞器、含磷酸盐化合物代谢过程等GO条目显著富集；差异表达下调的mRNA在跨膜信号受体活性、超分子纤维、组织发育等GO条目显著富集。KEGG富集分析显示差异表达上调的mRNA主要富集于胰岛素分泌、氧化磷酸化、帕金森病等信号通路；差异表达下调的mRNA主要富集于神经活性配体-受体相互作用、钙信号通路、酪氨酸代谢、苯丙氨酸代谢等信号通路。CeRNA网络显示circRNA_45921/miR-34c-5p/Eef2k调控网络可能在IAPP功能发挥中具有作用。

结论

腹腔注射IAPP改变AD小鼠和WT小鼠脑组织中circRNA和mRNA的表达谱。差异表达的Paip2、Cdon、Ttr和circRNA_45921/miR-34c-5p/Eef2k调控网络可能在IAPP调节AD的发生发展中起作用。

Abstract

Objective

To investigate the effects of intraperitoneal injection of islet amyloid polypeptide (IAPP) on the expression profiles of circular RNAs (circRNAs) and messenger RNAs (mRNAs) in the brain tissue of Alzheimer's disease (AD) mice and wild-type (WT) mice.

Methods

Six 10-month-old male APP/PS1 transgenic AD model and C57 WT mice (20~30 g) were employed in this study. They were randomly divided into 2 groups

and further assigned into AD+IAPP (AD mice with IAPP intraperitoneal injection)

WT+IAPP (WT mice with IAPP intraperitoneal injection)

AD+PBS (AD mice injected with same dose of PBS intraperitoneally) and WT+PBS (WT mice with intraperitoneal injection of PBS) groups (

=3). After the intervention

total RNA was extracted from the brain tissue of 4 groups of mice

and gene chip sequencing was performed to screen differentially expressed circRNAs and mRNAs between AD+IAPP and WT+IAPP mice and between AD+PBS and WT+PBS mice. Among the differentially expressed circRNAs between AD+IAPP and WT+IAPP mice

6 circRNAs were selected and subjected to real-time quantitative polymerase chain reaction (qRT-PCR) to verify the reliability of the microarray results. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway enrichment analysis were performed on the differentially expressed mRNAs. Subsequently

a competitive endogenous RNA (ceRNA) network was constructed for significantly differentially expressed circRNA_45921.

Results

There were 237 circRNAs significantly differentially expressed between AD+IAPP and WT+IAPP mice

of which 157 were up-regulated and 80 were down-regulated. Totally 663 significantly differentially expressed mRNAs were found

including 348 up-regulated and 315 down-regulated. The results of qRT-PCR showed that the differential expression of 6 circRNAs was consistent with the results of gene chip

indicating that the results of gene chip sequencing were reliable. GO enrichment analysis revealed that differentially up-regulated mRNAs were significantly enriched in nucleoside phosphate binding

organelles and metabolism processes of phosphate containing compounds. The differentially down-regulated mRNAs were significantly enriched in transmembrane signal receptor activity

supramolecular fibers and tissue development. KEGG enrichment analysis indicated that differentially upregulated mRNAs were mainly enriched in signal pathways such as insulin secretion

oxidative phosphorylation

and Parkinson's disease

while those down-regulated ones in signal pathways such as neuroactive ligand receptor interactions

calcium signaling pathways

tyrosine metabolism and phenylalanine metabolism. CeRNA network displayed that the circRNA_45921/miR-34c-5p/Eef2k regulatory network may play a role in the functioning of IAPP.

Conclusion

Intraperitoneal injection of IAPP alters the expression profiles of circRNA and mRNA in the brain tissues of AD mice and WT mice. Differentially expressed Paip2

Cdon

Ttr

and circRNA_45921/miR-34c-5p/Eef2k regulatory network may have regulatory roles in IAPP regulating the development of AD.

关键词

Keywords

references

KNOPMAN D S, AMIEVA H, PETERSEN R C, et al . Alzheimer disease[J ] . Nat Rev Dis Primers, 2021, 7: 33. DOI: 10.1038/s41572-021-00269-y.

2022 Alzheimer's disease facts and figures[J ] . Alzheimers Dement, 2022, 18(4): 700-789. DOI: 10.1002/alz.12638 http://dx.doi.org/10.1002/alz.12638 .

WESTERMARK P, ANDERSSON A, WESTERMARK G T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus[J]. Physiol Rev, 2011, 91(3): 795-826. DOI: 10.1152/physrev.00042.2009.

ZHANG Y, SONG W H. Islet amyloid polypeptide: another key molecule in Alzheimer's pathogenesis?[J]. Prog Neurobiol, 2017, 153: 100-120. DOI: 10.1016/j.pneurobio.2017.03.001.

MORENO-GONZALEZ I, EDWARDS Ⅲ G, SALVADORES N, et al . Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding[J ] . Mol Psychiatry, 2017, 22(9): 1327-1334. DOI: 10.1038/mp.2016.230.

KAPURNIOTU A. Enlightening amyloid fibrils linked to type 2 diabetes and cross-interactions with Aβ[J]. Nat Struct Mol Biol, 2020, 27(11): 1006-1008. DOI: 10.1038/s41594-020-00523-z.

HU R D, ZHANG M Z, CHEN H, et al . Cross-seeding interaction between β-amyloid and human islet amyloid polypeptide[J ] . ACS Chem Neurosci, 2015, 6(10): 1759-1768. DOI: 10.1021/acschemneuro.5b00192.

BHARADWAJ P, SOLOMON T, SAHOO B R, et al . Amylin and beta amyloid proteins interact to form amorphous hetero complexes with enhanced toxicity in neuronal cells[J ] . Sci Rep, 2020, 10: 10356. DOI: 10.1038/s41598-020-66602-9.

JACKSON K, BARISONE G A, DIAZ E, et al . Amylin deposition in the brain: a second amyloid in Alzheimer disease?[J ] . Ann Neurol, 2013, 74(4): 517-526. DOI: 10.1002/ana.23956.

YAN L M, VELKOVA A, TATAREK-NOSSOL M, et al . IAPP mimic blocks Abeta cytotoxic self-assembly: cross-suppression of amyloid toxicity of Abeta and IAPP suggests a molecular link between Alzheimer's disease and type Ⅱ diabetes[J ] . Angew Chem Int Ed Engl, 2007, 46(8): 1246-1252. DOI: 10.1002/anie.200604056.[PubMed ]

YAN L M, VELKOVA A, TATAREK-NOSSOL M, et al . Selectively N-methylated soluble IAPP mimics as potent IAPP receptor agonists and nanomolar inhibitors of cytotoxic self-assembly of both IAPP and Aβ40[J ] . Angewandte Chemie Int Ed, 2013, 52(39): 10378-10383. DOI: 10.1002/anie.201302840.

AFTABIZADEH M, TATAREK-NOSSOL M, ANDREETTO E, et al . Blocking inflammasome activation caused by β-amyloid peptide (aβ) and islet amyloid polypeptide (IAPP) through an IAPP mimic[J ] . ACS Chem Neurosci, 2019, 10(8): 3703-3717. DOI: 10.1021/acschemneuro.9b00260.

ZHU H, WANG X, WALLACK M, et al . Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impa irment and brain amyloid pathology in murine models of Alzheimer's disease[J ] . Mol Psychiatry, 2015, 20(2): 252-262. DOI: 10.1038/mp.2014.17.

ADLER B L, YARCHOAN M, HWANG H M, et al . Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition[J ] . Neurobiol Aging, 2014, 35(4): 793-801. DOI: 10.1016/j.neurobiolaging.2013.10.076.

SCHULTZ N, JANELIDZE S, BYMAN E, et al . Levels of islet amyloid polypeptide in cerebrospinal fluid and plasma from patients with Alzheimer's disease[J ] . PLoS One, 2019, 14(6): e0218561. DOI: 10.1371/journal.pone.0218561.

IDDA M L, MUNK R, ABDELMOHSEN K, et al . Noncoding RNAs in Alzheimer's disease[J ] . Wiley Interdiscip Rev RNA, 2018, 9(2): e1463. DOI: 10.1002/wrna.1463.

SONG C H, ZHANG Y F, HUANG W Y, et al . Circular RNA Cwc27 contributes to Alzheimer's disease pathogenesis by repressing Pur-α activity[J ] . Cell Death Differ, 2022, 29(2): 393-406. DOI: 10.1038/s41418-021-00865-1.

MO D D, LI X P, RAABE C A, et al . Circular RNA encoded amyloid beta peptides-a novel putative player in alzheimer's disease[J ] . Cells, 2020, 9(10): 2196. DOI: 10.3390/cells9102196.

BHAGAT V, VERCHERE C B. A small molecule improves diabetes in mice expressing human islet amyloid polypeptide[J]. Islets, 2023, 15(1): 12-15. DOI: 10.1080/19382014.2022.2163829.

BOCCARDI V, MURASECCO I, MECOCCI P. Diabetes drugs in the fight against Alzheimer's disease[J]. Ageing Res Rev, 2019, 54: 100936. DOI: 10.1016/j.arr.2019.100936.

YOSHIKAWA T, WU J F, OTSUKA M, et al . ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression[J ] . Nucleic Acids Res, 2015, 43(15): 7577-7589. DOI: 10.1093/nar/gkv728..

SHIM S M, KOH Y H, KIM J H, et al . Author Correction: a combination of multiple autoantibodies is associated with the risk of Alzheimer's disease and cognitive impairment[J ] . Sci Rep, 2022, 12: 2328. DOI: 10.1038/s41598-021-04556-2.

ULUCA B, LEKTEMUR ESEN C, SARITAS ERDOGAN S, et al . NFI transcriptionally represses CDON and is required for SH-SY 5 Y cell survival[J ] . Biochim Biophys A cta Gene Regul Mech, 2022, 1865(2): 194798. DOI: 10.1016/j.bbagrm.2022.194798..

CHAPOULY C, HOLLIER PL, GUIMBAL S, et al . Desert hedgehog-driven endothelium integrity is enhanced by Gas1 (growth arrest-specific 1) but negatively regulated by Cdon (cell adhesion molecule-related/downregulated by oncogenes)[J ] . Arterioscler Thromb Vasc Biol, 2020, 40(12): e336-e349. DOI: 10.1161/ATVBAHA.120.314441.

SOUSA J C, CARDOSO I, MARQUES F, et al . Transthyretin and Alzheimer's disease: where in the brain?[J ] . Neurobiol Aging, 2007, 28(5): 713-718. DOI: 10.1016/j.neurobiolaging.2006.03.015.

ZISKIN J L, GREICIUS M D, ZHU W, et al . Neuropathologic analysis of Tyr69His TTR variant meningovascular amyloidosis with dementia[J ] . Acta Neuropathol Commun, 2015, 3: 43. DOI: 10.1186/s40478-015-0216-0.

张国新, 彭琴玉, 郭笑迪, 等. 胰岛淀粉样多肽在阿尔茨海默病发病机制中的作用研究进展[J]. 卒中与神经疾病, 2022, 29(3):291-295, 299. DOI: 10.3969/j.issn.1007-0478.2022.03.019.

ZHANG G X, PENG Q Y, GUO X D, et al . Research progress on the role of islet amyloid polypeptide in the pathogenesis of Alzheimer’s disease[J ] . Stroke Nerv Dis, 2022, 29(3): 291-295, 299. DOI: 10.3969/j.issn.1007-0478.2022.03.019.

RYBAK-WOLF A, STOTTMEISTER C, GLAŽARP, et al . Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed[J ] . Mol Cell, 2015, 58(5): 870-885. DOI: 10.1016/j.molcel.2015.03.027.

YANG X B, LI X Y, ZHONG C H, et al . Circular RNA circPHKA2 relieves OGD-induced human brain microvascular endothelial cell injuries through competitively binding miR-574-5p to modulate SOD2[J ] . Oxid Med Cell Longev, 2021, 2021: 3823122. DOI: 10.1155/2021/3823122.

KU T, LI B, GAO R, et al . NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration[J ] . Part Fibre Toxicol, 2017, 14(1): 34. DOI: 10.1186/s12989-017-0215-3.

LU D, XU A D. Mini review: circular RNAs as potential clinical biomarkers for disorders in the central nervous system[J]. Front Genet, 2016, 7: 53. DOI: 10.3389/fgene.2016.00053.

BRENDER J R, SALAMEKH S, RAMAMOORTHY A. Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective[J]. Acc Chem Res, 2012, 45(3): 454-462. DOI: 10.1021/ar200189b.

PRUZIN J J, NELSON P T, ABNER E L, et al . Review: Relationship of type 2 diabetes to human brain pathology[J ] . Neuropathol Appl Neurobiol, 2018, 44(4): 347-362. DOI: 10.1111/nan.12476.

ANGUIANO M, NOWAK R J, LANSBURY P T Jr. Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type Ⅱ diabetes[J]. Biochemistry, 2002, 41(38): 11338-11343. DOI: 10.1021/bi020314u.

ZHANG G, MENG L, WANG Z, et al . Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer's disease[J ] . Mol Neurodegener, 2022, 17(1): 12. DOI: 10.1186/s13024-022-00518-y.

WU H, HUANG M, LU M J, et al . Regulation of microtubule-associated protein tau (MAPT) by miR-34c-5p determines the chemosensitivity of gastric cancer to paclitaxel[J ] . Cancer Chemother Pharmacol, 2013, 71(5): 1159-1171. DOI: 10.1007/s00280-013-2108-y.

BECKELMAN B C, YANG W Z, KASICA N P, et al . Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer's disease model mice[J ] . J Clin Investig, 2019, 12 9(2): 820-833. DOI: 10.1172/jci122954.

ANKARCRONA M, WINBLAD B, MONTEIRO C, et al . Current and future treatment of amyloid diseases[J ] . J Intern Med, 2016, 280(2): 177-202. DOI: 10.1111/joim.12506.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

胰淀素在痴呆小鼠和正常小鼠脑内的分布和表达变化

胰淀素对阿尔茨海默病小鼠学习和记忆能力以及Akt信号通路的影响

颈深淋巴-静脉吻合术治疗阿尔茨海默病的病例系列报道

circ-Tns3/miR-671-5p/sirt1轴介导阿尔茨海默病神经元损伤的分子机制

骨钙素在阿尔茨海默病细胞模型中的神经保护作用与机制研究