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Original Article

Exp Neurobiol 2023; 32(4): 259-270

Published online August 31, 2023

© The Korean Society for Brain and Neural Sciences

Presenilin 2 N141I Mutation Induces Hyperimmunity by Immune Cell-specific Suppression of REV-ERBα without Altering Central Circadian Rhythm

Hyeri Nam, Boil Kim, Younghwan Lee, Han Kyoung Choe* and Seong-Woon Yu*

Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea

Correspondence to: *To whom correspondence should be addressed.
Han Kyoung Choe, TEL: 82-53-785-6150, FAX: 82-53-785-6109
Seong-Woon Yu, TEL: 82-53-785-6113, FAX: 82-53-785-6109
These authors contributed equally to this article.

Received: April 12, 2023; Revised: June 21, 2023; Accepted: July 7, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Circadian rhythm is a 24-hour cycle of behavioral and physiological changes. Disrupted sleep-wake patterns and circadian dysfunction are common in patients of Alzheimer Disease (AD) and are closely related with neuroinflammation. However, it is not well known how circadian rhythm of immune cells is altered during the progress of AD. Previously, we found presenilin 2 (Psen2) N141I mutation, one of familial AD (FAD) risk genes, induces hyperimmunity through the epigenetic repression of REV-ERBα expression in microglia and bone marrow-derived macrophage (BMDM) cells. Here, we investigated whether repression of REV-ERBα is associated with dysfunction of immune cell-endogenous or central circadian rhythm by analyses of clock genes expression and cytokine secretion, bioluminescence recording of rhythmic PER2::LUC expression, and monitoring of animal behavioral rhythm. Psen2 N141I mutation down-regulated REV-ERBα and induced selective over-production of IL-6 (a well-known clock-dependent cytokine) following the treatment of toll-like receptor (TLR) ligands in microglia, astrocytes, and BMDM. Psen2 N141I mutation also lowered amplitude of intrinsic daily oscillation in these immune cells representatives of brain and periphery. Of interest, however, the period of daily rhythm remained intact in immune cells. Furthermore, analyses of the central clock and animal behavioral rhythms revealed that central clock remained normal without down-regulation of REV-ERBα. These results suggest that Psen2 N141I mutation induces hyperimmunity mainly through the suppression of REV-ERBα in immune cells, which have lowered amplitude but normal period of rhythmic oscillation. Furthermore, our data reveal that central circadian clock is not affected by Psen2 N141I mutation.

Graphical Abstract

Keywords: Circadian rhythm, Presenilin 2, Alzheimer disease, Hyperimmunity, REV-ERBα