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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
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    References listed on IDEAS

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    1. Steven M. Reppert & David R. Weaver, 2002. "Coordination of circadian timing in mammals," Nature, Nature, vol. 418(6901), pages 935-941, August.
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