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

Hyperimmunity drives the development of Alzheimer disease (AD). The immune system is under the circadian control, and circadian abnormalities aggravate AD progress. Here, we investigated how an AD-linked mutation deregulates expression of circadian genes and induces cognitive decline using the knock-in (KI) mice heterozygous for presenilin 2 (Psen2) N141I mutation. This mutation causes overproduction of clock-controlled cytokines through the epigenetic repression of the clock protein REV-ERBα in innate immune cells, which show normal circadian period but lower amplitude. The KI/+ mice displayed normal circadian behaviour patterns, but were vulnerable to an otherwise innocuous, mild immune challenge. The antipsychotic chlorpromazine restored the REV-ERBα level and prevented the overexcitation of innate immune cells and cognitive decline in KI/+ mice. These results highlight a new pathogenic link between this AD mutation and immune cell-intrinsic circadian alteration through the epigenetic suppression of REV-ERBα.