| First Author | Nam H | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 1972 |
| PubMed ID | 35418126 | Mgi Jnum | J:325409 |
| Mgi Id | MGI:7265911 | Doi | 10.1038/s41467-022-29653-2 |
| Citation | Nam H, et al. (2022) Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBalpha. Nat Commun 13(1):1972 |
| abstractText | 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-ERBalpha in innate immune cells. The KI/+ mice are vulnerable to otherwise innocuous, mild immune challenges. The antipsychotic chlorpromazine restores the REV-ERBalpha 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-ERBalpha. |
