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

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 and Seong-Woon Yu ()
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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)
Han Kyoung Choe: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Seong-Woon Yu: Daegu Gyeongbuk Institute of Science and Technology (DGIST)

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29653-2

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