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Spatial transcriptomics identifies regional disruptions in brain rhythmic gene expression in a mouse model of Alzheimer’s disease

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that impairs memory, cognitive function, and the ability to perform everyday activities. In addition to cognitive decline, behavioral disturbances in the sleep-wake cycle such as progressive fragmentation of sleep, decreased total sleep time, and increased confusion or restlessness in the evening (sundowning) are a hallmark of AD. Emerging evidence suggests that these disruptions in sleep and behavior may be underpinned by molecular dysregulation of the circadian clock. Here, we utilize Visium spatial transcriptomics to characterize diurnal transcriptional rhythms across various brain regions in APP23 transgenic mice, a model of AD, and their non-transgenic littermates in 7- and 14-month old mice. We reveal significant alterations in rhythmic gene expression in APP23-TG mice, particularly in the hippocampus and cortex. These changes were evident in 7-month-old animals, coinciding with early amyloid deposition and persisted with advancing pathology. This study offers novel insights into the large-scale dysregulation of rhythmic gene expression in AD, highlighting molecular pathways connected to circadian disruption at various stages of the disease. It underscores the potential role of these disruptions in AD progression and opens new avenues for diagnosis, treatment, and management.

ORGANISM(S): Mus musculus

PROVIDER: GSE282203 | GEO | 2026/03/13

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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Spatial transcriptomics identifies regional disruptions in brain rhythmic gene expression in a mouse model of Alzheimer’s disease

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