IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29653-2.html
   My bibliography  Save this article

Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Author

Listed:
  • Hyeri Nam

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Younghwan Lee

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Boil Kim

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Ji-Won Lee

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Seohyeon Hwang

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Hyun-Kyu An

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Kyung Min Chung

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Youngjin Park

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Jihyun Hong

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Kyungjin Kim

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Eun-Kyoung Kim

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST)
    Neurometabolomics Research Center, DGIST)

  • Han Kyoung Choe

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Seong-Woon Yu

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

Abstract

Hyperimmunity drives the development of Alzheimer disease (AD). The immune system is under the circadian control, and circadian abnormalities aggravate AD progress. Here, we investigate how an AD-linked mutation deregulates expression of circadian genes and induces cognitive decline using the knock-in (KI) mice heterozygous for presenilin 2 N141I mutation. This mutation causes selective overproduction of clock gene-controlled cytokines through the DNA hypermethylation-mediated repression of REV-ERBα in innate immune cells. The KI/+ mice are vulnerable to otherwise innocuous, mild immune challenges. The antipsychotic chlorpromazine restores the REV-ERBα level by normalizing DNA methylation through the inhibition of PI3K/AKT1 pathway, and prevents the overexcitation of innate immune cells and cognitive decline in KI/+ mice. These results highlight a pathogenic link between this AD mutation and immune cell overactivation through the epigenetic suppression of REV-ERBα.

Suggested Citation

  • Hyeri Nam & Younghwan Lee & Boil Kim & Ji-Won Lee & Seohyeon Hwang & Hyun-Kyu An & Kyung Min Chung & Youngjin Park & Jihyun Hong & Kyungjin Kim & Eun-Kyoung Kim & Han Kyoung Choe & Seong-Woon Yu, 2022. "Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29653-2
    DOI: 10.1038/s41467-022-29653-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29653-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-29653-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Steven M. Reppert & David R. Weaver, 2002. "Coordination of circadian timing in mammals," Nature, Nature, vol. 418(6901), pages 935-941, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Cheng-Kang Chiang & Neel Mehta & Abhilasha Patel & Peng Zhang & Zhibin Ning & Janice Mayne & Warren Y L Sun & Hai-Ying M Cheng & Daniel Figeys, 2014. "The Proteomic Landscape of the Suprachiasmatic Nucleus Clock Reveals Large-Scale Coordination of Key Biological Processes," PLOS Genetics, Public Library of Science, vol. 10(10), pages 1-15, October.
    2. Valerie L Harbour & Yuval Weigl & Barry Robinson & Shimon Amir, 2013. "Comprehensive Mapping of Regional Expression of the Clock Protein PERIOD2 in Rat Forebrain across the 24-h Day," PLOS ONE, Public Library of Science, vol. 8(10), pages 1-14, October.
    3. O. Slaby & S. Sager & O. S. Shaik & U. Kummer & D. Lebiedz, 2007. "Optimal control of self-organized dynamics in cellular signal transduction," Mathematical and Computer Modelling of Dynamical Systems, Taylor & Francis Journals, vol. 13(5), pages 487-502, October.
    4. Michal Dudek & Dharshika R. J. Pathiranage & Beatriz Bano-Otalora & Anna Paszek & Natalie Rogers & Cátia F. Gonçalves & Craig Lawless & Dong Wang & Zhuojing Luo & Liu Yang & Farshid Guilak & Judith A., 2023. "Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Jing Wang & Haibo Di & Steven Laureys & Nantu Hu, 2018. "Circadian Rhythm of Patients with Disorders of Consciousness," Open Access Journal of Neurology & Neurosurgery, Juniper Publishers Inc., vol. 9(3), pages 60-61, November.
    6. Li, Ying & Liu, Zengrong, 2016. "Coupling mechanism in the gate and oscillator model of the SCN," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 457(C), pages 62-72.
    7. Valerie L Harbour & Yuval Weigl & Barry Robinson & Shimon Amir, 2014. "Phase Differences in Expression of Circadian Clock Genes in the Central Nucleus of the Amygdala, Dentate Gyrus, and Suprachiasmatic Nucleus in the Rat," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-9, July.
    8. Nguyen, Ha Trong & Zubrick, Stephen R. & Mitrou, Francis, 2022. "The effects of sleep duration on child health and development," GLO Discussion Paper Series 1150, Global Labor Organization (GLO).
    9. Kathyani Parasram & Amy Zuccato & Minjeong Shin & Reegan Willms & Brian DeVeale & Edan Foley & Phillip Karpowicz, 2024. "The emergence of circadian timekeeping in the intestine," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Michael Savic & Rowan P. Ogeil & Megan J. Sechtig & Peta Lee-Tobin & Nyssa Ferguson & Dan I. Lubman, 2019. "How Do Nurses Cope with Shift Work? A Qualitative Analysis of Open-Ended Responses from a Survey of Nurses," IJERPH, MDPI, vol. 16(20), pages 1-17, October.
    11. Jos H T Rohling & Henk Tjebbe vanderLeest & Stephan Michel & Mariska J Vansteensel & Johanna H Meijer, 2011. "Phase Resetting of the Mammalian Circadian Clock Relies on a Rapid Shift of a Small Population of Pacemaker Neurons," PLOS ONE, Public Library of Science, vol. 6(9), pages 1-9, September.
    12. Sherin Al-Safadi & Aya Al-Safadi & Marie Branchaud & Spencer Rutherford & Arun Dayanandan & Barry Robinson & Shimon Amir, 2014. "Stress-Induced Changes in the Expression of the Clock Protein PERIOD1 in the Rat Limbic Forebrain and Hypothalamus: Role of Stress Type, Time of Day, and Predictability," PLOS ONE, Public Library of Science, vol. 9(10), pages 1-16, October.
    13. Jean-Pierre Etchegaray & Elizabeth A Yu & Premananda Indic & Robert Dallmann & David R Weaver, 2010. "Casein Kinase 1 Delta (CK1δ) Regulates Period Length of the Mouse Suprachiasmatic Circadian Clock In Vitro," PLOS ONE, Public Library of Science, vol. 5(4), pages 1-6, April.
    14. Francesco Riganello & Valeria Prada & Andres Soddu & Carol di Perri & Walter G. Sannita, 2019. "Circadian Rhythms and Measures of CNS/Autonomic Interaction," IJERPH, MDPI, vol. 16(13), pages 1-11, July.
    15. Purificación Gómez-Abellán & Antoni Díez-Noguera & Juan A Madrid & Juan A Luján & José M Ordovás & Marta Garaulet, 2012. "Glucocorticoids Affect 24 h Clock Genes Expression in Human Adipose Tissue Explant Cultures," PLOS ONE, Public Library of Science, vol. 7(12), pages 1-10, December.
    16. Qiang Bao & Di Liu & Yujiao Guo & Wang Gu & Zhengfeng Cao & Yu Zhang & Yang Zhang & Qi Xu & Guohong Chen, 2023. "Melatonin Secretion in Regulating the Circadian Rhythms of Reproduction in Goose ( Anser cygnoides )," Agriculture, MDPI, vol. 13(8), pages 1-16, August.
    17. Francisco J Sánchez Muniz & Cristina Simón Martín, 2017. "Clock Genes, Chronodisruption, Nutrition and Obesity," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 3(2), pages 1-62:3, July.
    18. Henson, Michael A., 2013. "Multicellular models of intercellular synchronization in circadian neural networks," Chaos, Solitons & Fractals, Elsevier, vol. 50(C), pages 48-64.
    19. Andrew E. Warfield & Pooja Gupta & Madison M. Ruhmann & Quiana L. Jeffs & Genevieve C. Guidone & Hannah W. Rhymes & McKenzi I. Thompson & William D. Todd, 2023. "A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Li, Ying & Liu, Zengrong, 2015. "Dynamical mechanism of Bmal1/Rev-erbα loop in circadian clock," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 430(C), pages 126-135.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29653-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.