Circadian rhythm sleep disorders and time-of-day-dependent memory deficiency in Presenilin1/2 conditional knockout mice with long noncoding RNA expression profiling changes

Alzheimer's disease (AD) patients exhibit sleep and circadian disturbances prior to the onset of cognitive decline, and these disruptions worsen with disease severity. However, the molecular mechanisms behind sleep and circadian disruptions in AD patients are poorly understood. In this study, we investigated sleep pattern and circadian rhythms in Presenilin-1/2 conditional knockout (DKO) mice. Assessment of EEG and EMG recordings showed that DKO mice displayed increased NREM sleep time but not REM sleep during the dark phase compared to WT mice at the age of two months; at the age of six months, the DKO mice showed increased wakefulness periods and decreased total time spent in both NREM and REM sleep. WT exhibited time-of-day dependent modulation of contextual and cued memory. Compared with WT mice, 4-month-old DKO mice exhibited the deficiency regardless trained and tested in the same light/night phase or not. Particularly interesting was that DKO showed circadian modulation deficiency when trained in the resting period but not in the active period. Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides, and they have rhythmic expression in mammals. To date no study has investigated rhythmic lncRNA expression in Alzheimer's disease. We applied RNA-seq technology to profile hippocampus expression of lncRNAs in DKO mice during the light (/resting) and dark (/active) phases and performed gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the cis lncRNA targets. Expression alteration of lncRNAs associated with immune response and metallodipeptidase activity may contribute to the circadian disruptions of DKO mice. Especially we identified some LncRNAs which expression change oppositely between day and light in DKO mice compared to WT mice and are worthy to be studied further. Our results exhibited the circadian rhythm sleep disorders and a noteworthy time-of-day-dependent memory deficiency in AD model mice and provide a useful resource for studying the expression and function of lncRNAs during circadian disruptions in Alzheimer's disease.