{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:32:42Z","timestamp":1791952362194,"version":"4.3.4"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Circadian rhythm disruption (CRD) represents a critical contributor to the pathogenesis of Alzheimer\u2019s disease (AD). Nonetheless, how CRD functions within the AD immune microenvironment remains to be illustrated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Circadian rhythm score (CRscore) was utilized to quantify the microenvironment status of circadian disruption in a single-cell RNA sequencing dataset derived from AD. Bulk transcriptome datasets from public repository were employed to validate the effectiveness and robustness of CRscore. A machine learning-based integrative model was applied for constructing a characteristic CRD signature, and RT-PCR analysis was employed to validate their expression levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We depicted the heterogeneity in B cells, CD4<jats:sup>+<\/jats:sup> T cells, and CD8<jats:sup>+<\/jats:sup> T cells based on the CRscore. Furthermore, we discovered that CRD might be strongly linked to the immunological and biological features of AD, as well as the pseudotime trajectories of major immune cell subtypes. Additionally, cell\u2013cell interactions revealed that CRD was critical in the alternation of ligand-receptor pairs. Bulk sequencing analysis indicated that the CRscore was found to be a reliable predictive biomarker in AD patients. The characteristic CRD signature, which included 9 circadian\u2010related genes (CRGs), was an independent risk factor that accurately predicted the onset of AD. Meanwhile, abnormal expression of several characteristic CRGs, including GLRX, MEF2C, PSMA5, NR4A1, SEC61G, RGS1, and CEBPB, was detected in neurons treated with A\u03b21-42 oligomer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study revealed CRD-based cell subtypes in the AD microenvironment at single-cell level and proposed a robust and promising CRD signature for AD diagnosis. A deeper knowledge of these mechanisms may provide novel possibilities for incorporating \u201ccircadian rhythm-based anti-dementia therapies\u201d into the treatment protocols of individualized medicine.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1182307","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T06:12:15Z","timestamp":1683871935000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Combined analysis of single-cell and bulk RNA sequencing reveals the expression patterns of circadian rhythm disruption in the immune microenvironment of Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Huiling","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxia","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeming","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichao","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjiong","family":"Ou-Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meili","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/alz.12328","article-title":"2021 alzheimer's disease facts and figures","volume":"17","year":"2021","journal-title":"Alzheimers Dement"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.5847","article-title":"Amyloid-\u03b2 and tau: the trigger and bullet in Alzheimer disease pathogenesis","volume":"71","author":"Bloom","year":"2014","journal-title":"JAMA Neurol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.16-3-247","article-title":"Drug treatments in alzheimer's disease","volume":"16","author":"Briggs","year":"2016","journal-title":"Clin Med (Lond)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2011.601740","article-title":"Pharmacologists and Alzheimer disease therapy: to boldly go where no scientist has gone before","volume":"20","author":"Mancuso","year":"2011","journal-title":"Expert Opin Investig Drugs"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1195027","article-title":"Circadian integration of metabolism and energetics","volume":"330","author":"Bass","year":"2010","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13028","article-title":"Chronic sleep deprivation altered the expression of circadian clock genes and aggravated alzheimer's disease neuropathology","volume":"32","author":"Niu","year":"2022","journal-title":"Brain Pathol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70317","article-title":"Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration","volume":"123","author":"Musiek","year":"2013","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s13024-015-0007-x","article-title":"A\u03b2-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in alzheimer's disease","volume":"10","author":"Song","year":"2015","journal-title":"Mol Neurodegener"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8479-6","article-title":"Acceleration of the development of alzheimer's disease in amyloid beta-infused peroxiredoxin 6 overexpression transgenic mice","volume":"48","author":"Yun","year":"2013","journal-title":"Mol Neurobiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s13311-021-01031-8","article-title":"Circadian rhythm sleep-wake disorders: a contemporary review of neurobiology, treatment, and dysregulation in neurodegenerative disease","volume":"18","author":"Steele","year":"2021","journal-title":"Neurotherapeutics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41582-021-00577-7","article-title":"Circadian rhythms in neurodegenerative disorders","volume":"18","author":"Nassan","year":"2022","journal-title":"Nat Rev Neurol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/B978-0-12-819975-6.00018-2","article-title":"Circadian changes in alzheimer's disease: neurobiology, clinical problems, and therapeutic opportunities","volume":"179","author":"Toljan","year":"2021","journal-title":"Handb Clin Neurol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1046410","article-title":"Identification of immune microenvironment subtypes and signature genes for alzheimer's disease diagnosis and risk prediction based on explainable machine learning","volume":"13","author":"Lai","year":"2022","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"101409","DOI":"10.1016\/j.arr.2021.101409","article-title":"The role of the immune system in alzheimer's disease","volume":"70","author":"Wu","year":"2021","journal-title":"Ageing Res Rev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.12.044","article-title":"Molecular interactions between components of the circadian clock and the immune system","volume":"432","author":"Hergenhan","year":"2020","journal-title":"J Mol Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00185","article-title":"Expression of the circadian clock gene BMAL1 positively correlates with antitumor immunity and patient survival in metastatic melanoma","volume":"8","author":"de Assis","year":"2018","journal-title":"Front Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1161","article-title":"CircaDB: a database of mammalian circadian gene expression profiles","volume":"41","author":"Pizarro","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12803","article-title":"Single-cell transcriptomic analysis reveals circadian rhythm disruption associated with poor prognosis and drug-resistance in lung adenocarcinoma","volume":"73","author":"He","year":"2022","journal-title":"J Pineal Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1534-8_10","article-title":"Inference of gene regulatory network from single-cell transcriptomic data using pySCENIC","volume":"2328","author":"Kumar","year":"2021","journal-title":"Methods Mol Biol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","article-title":"The single-cell transcriptional landscape of mammalian organogenesis","volume":"566","author":"Cao","year":"2019","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an r package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B22","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41467-017-02391-6","article-title":"Perturbation-response genes reveal signaling footprints in cancer gene expression","volume":"9","author":"Schubert","year":"2018","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.934494","article-title":"Necroptosis identifies novel molecular phenotypes and influences tumor immune microenvironment of lung adenocarcinoma","volume":"13","author":"Zhao","year":"2022","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71880","article-title":"A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer","volume":"11","author":"Yang","year":"2022","journal-title":"Elife"},{"key":"B25","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/s41467-022-28421-6","article-title":"Machine learning-based integration develops an immune-derived lncRNA signature for improving outcomes in colorectal cancer","volume":"13","author":"Liu","year":"2022","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","first-page":"101503","DOI":"10.1016\/j.redox.2020.101503","article-title":"Restoration of l-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function","volume":"34","author":"Lai","year":"2020","journal-title":"Redox Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1957407","DOI":"10.1080\/19490976.2021.1957407","article-title":"Sleep, circadian rhythm and gut microbiota: alterations in alzheimer's disease and their potential links in the pathogenesis","volume":"13","author":"Li","year":"2021","journal-title":"Gut Microbes"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2174\/18756190MTA21MjAf3","article-title":"Circadian rhythm disruption and alzheimer's disease: the dynamics of a vicious cycle","volume":"19","author":"Sharma","year":"2021","journal-title":"Curr Neuropharmacol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5344","DOI":"10.1038\/s41467-018-07735-4","article-title":"JunB regulates homeostasis and suppressive functions of effector regulatory T cells","volume":"9","author":"Koizumi","year":"2018","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636510","article-title":"ICER\/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells","volume":"37","author":"Bodor","year":"2007","journal-title":"Eur J Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2185","DOI":"10.1038\/s41467-021-22479-4","article-title":"Therapeutic b-cell depletion reverses progression of alzheimer's disease","volume":"12","author":"Kim","year":"2021","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.bbi.2020.05.070","article-title":"CD8(+) T-cells infiltrate alzheimer's disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice","volume":"89","author":"Unger","year":"2020","journal-title":"Brain Behav Immun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1177\/10738584211024907","article-title":"T Cells: a growing universe of roles in neurodegenerative diseases","volume":"28","author":"Dressman","year":"2022","journal-title":"Neuroscientist"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1907167","article-title":"The role of mitophagy in the regulation of mitochondrial energetic status in neurons","volume":"17","author":"Han","year":"2021","journal-title":"Autophagy"},{"key":"B35","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1172\/JCI120848","article-title":"Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas","volume":"129","author":"Area-Gomez","year":"2019","journal-title":"J Clin Invest"},{"key":"B36","doi-asserted-by":"publisher","first-page":"107808","DOI":"10.1016\/j.intimp.2021.107808","article-title":"Andrographolide ameliorates neuroinflammation in APP\/PS1 transgenic mice","volume":"96","author":"Zhang","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12567","article-title":"Progranulin mutations in clinical and neuropathological alzheimer's disease","volume":"18","author":"Vardarajan","year":"2022","journal-title":"Alzheimers Dement"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13511","article-title":"Insights into T-cell dysfunction in alzheimer's disease","volume":"20","author":"Dai","year":"2021","journal-title":"Aging Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.02.009","article-title":"T-Cell brain infiltration and immature antigen-presenting cells in transgenic models of alzheimer's disease-like cerebral amyloidosis","volume":"54","author":"Ferretti","year":"2016","journal-title":"Brain Behav Immun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0165-5728(01)00496-9","article-title":"Occurrence of T cells in the brain of alzheimer's disease and other neurological diseases","volume":"124","author":"Togo","year":"2002","journal-title":"J Neuroimmunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12103","article-title":"CD4 T cells in immunity and immunotherapy of alzheimer's disease","volume":"139","author":"Monsonego","year":"2013","journal-title":"Immunology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"880","DOI":"10.3390\/pharmaceutics12090880","article-title":"Drugs modulating CD4+ T cells blood-brain barrier interaction in alzheimer's disease","volume":"12","author":"Kubick","year":"2020","journal-title":"Pharmaceutics"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/08820139.2022.2136525","article-title":"Interleukin-17 promotes the infiltration of CD8+ T cells into the brain in a mouse model for alzheimer's disease","volume":"2022","author":"Ye","year":"2023","journal-title":"Immunol Invest"},{"key":"B44","doi-asserted-by":"publisher","first-page":"8972","DOI":"10.3390\/ijms23168972","article-title":"The pivotal role of NF-kB in the pathogenesis and therapeutics of alzheimer's disease","volume":"23","author":"Sun","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B45","doi-asserted-by":"publisher","first-page":"12050","DOI":"10.1038\/s41598-018-30487-6","article-title":"IL-1\u03b2, IL-6, TNF- \u03b1 and CRP in elderly patients with depression or alzheimer's disease: systematic review and meta-analysis","volume":"8","author":"Ng","year":"2018","journal-title":"Sci Rep"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.835288","article-title":"Post-translational modifications of the p53 protein and the impact in alzheimer's disease: a review of the literature","volume":"14","author":"Clark","year":"2022","journal-title":"Front Aging Neurosci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"5911","DOI":"10.3390\/ijms22115911","article-title":"When good kinases go rogue: GSK3, p38 MAPK and CDKs as therapeutic targets for alzheimer's and huntington's disease","volume":"22","author":"D'Mello","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-201448","article-title":"Role of hypoxia inducible factor-1\u03b1 in alzheimer's disease","volume":"80","author":"Wang","year":"2021","journal-title":"J Alzheimers Dis"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009933","article-title":"NF-\u03baB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1","volume":"17","author":"Shen","year":"2021","journal-title":"PloS Genet"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2020.02.006","article-title":"Effects of housing conditions and circadian time on baseline c-fos immunoreactivity in C57BL\/6J mice","volume":"431","author":"Robins","year":"2020","journal-title":"Neuroscience"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0610","article-title":"Evidence for circadian regulation of activating transcription factor 5 but not tyrosine hydroxylase by the chromaffin cell clock","volume":"148","author":"Lemos","year":"2007","journal-title":"Endocrinology"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2015.11.007","article-title":"TNF induced inhibition of cirbp expression depends on RelB NF-\u03baB signalling pathway","volume":"5","author":"Lopez","year":"2016","journal-title":"Biochem Biophys Rep"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180766","article-title":"Treatment combinations for alzheimer's disease: current and future pharmacotherapy options","volume":"67","author":"Cummings","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"B54","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/S1474-4422(20)30412-9","article-title":"APOE and alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches","volume":"20","author":"Serrano-Pozo","year":"2021","journal-title":"Lancet Neurol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1586\/14737159.2015.1002469","article-title":"Genetic diagnosis and prognosis of alzheimer's disease: challenges and opportunities","volume":"15","author":"Reitz","year":"2015","journal-title":"Expert Rev Mol Diagn"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.07.001","article-title":"Circadian rhythm disruption promotes lung tumorigenesis","volume":"24","author":"Papagiannakopoulos","year":"2016","journal-title":"Cell Metab"},{"key":"B57","doi-asserted-by":"publisher","first-page":"5116","DOI":"10.3390\/cancers14205116","article-title":"Circadian rhythm disruption as a contributor to racial disparities in prostate cancer","volume":"14","author":"Dasari","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B58","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/978-1-4939-8751-1_10","article-title":"Epigenetic basis of circadian rhythm disruption in cancer","volume":"1856","author":"Reszka","year":"2018","journal-title":"Methods Mol Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1182307\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T06:12:20Z","timestamp":1683871940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1182307\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,12]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2023.1182307"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1182307","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,12]]},"article-number":"1182307"}}