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

Psen2
^N141I/+ mice overproduce clock gene-controlled cytokines in response to LPS

To investigate the pathogenic function of the Psen2 N141I mutation in vivo, we generated KI mice harboring the Psen2 N141I allele (Psen2^N141I/+ and Psen2^N141I/N141I) (Fig. 1a). The substitution of N to I (AAC to ATC) was confirmed by genomic sequencing (Fig. 1b). Human AD patients with FAD mutations are heterozygous³⁰. Therefore, to more accurately recapitulate human AD and maintain the endogenous expression level, we used heterozygous Psen2^N141I/+ (KI/+) mice for all experiments. The protein and mRNA levels of PSEN2 in KI/+ primary microglia and bone marrow-derived macrophages (BMDM) were comparable to those in WT cells (Supplementary Fig. 1a, b), indicating that the N141I mutation did not affect PSEN2 expression. Also, this mutation did not…