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Circadian modulation by time-restricted feeding restores brain transcription and slows amyloid deposition in a mouse model of Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology, hippocampal transcription, and memory in two transgenic mouse models of Alzheimer’s disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing time-of-day transcription of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the multifactorial effects of timed feeding, which has far-reaching impact beyond metabolism and affects the brain as the substrate for neurodegeneration, including the alignment of circadian rhythmicity. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE236731 | GEO | 2023/08/11

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) patients exhibit sleep and circadian disturbances before cognitive decline, and these disruptions worsen with disease severity. However, the molecular mechanisms of sleep and circadian disruptions in AD patients are poorly understood. In this study, we investigated the sleep pattern and circadian rhythms in Presenilin-1/2 conditional knockout mice (DKO mice). Assessment of EEG and EMG recording showed that DKO mice exhibit sleep disorders from 2 months of age that worsen at the age of 6 months. The actogram of wheel running activity of DKO mice manifested movement splitting both in Dark and Light phases during the 24-hour light/dark cycle compared to WT mice. Notably, DKO mice also displayed increased NREM sleep time during the dark phase compared to WT mice at the age of two months; however, REM sleep showed no change in either WT or DKO littermates in the dark phase. When sleep and wakefulness were examined at the age of 6 months, the DKO mice showed increased wakefulness time and decreased total time spent in NREM and REM sleep. Analysis of the circadian modulation of memory revealed that the recall for contextual fear memory trained at ZT2 in WT mice was greater at ZT2 than at ZT14; however, the DKO mice had the same freezing responses with respect to both ZT2 and ZT14. Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides, and they have rhythmic expression in mammals. However, no study has investigated rhythmic lncRNA expression in Alzheimer’s disease so we applied RNA-seq technology to profile the expression of lncRNAs in the hippocampus of DKO mice in the light (resting) phase and dark (active) phase. Furthermore, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the biological process, cell component and molecular function of these differentially expressed lncRNAs (DE-lncRNAs). These results provide a useful resource for studying lncRNAs in circadian disruptions in Alzheimer’s disease.

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Circadian modulation by time-restricted feeding restores brain transcription and slows amyloid deposition in a mouse model of Alzheimer’s disease

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