Background: In addition to cognitive decline, Alzheimer’s Disease (AD) is also characterized by
agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and
have been referred to as ‘sundowning’. They are especially difficult for carers and there are no specific drug
treatments. There is increasing evidence that these symptoms reflect pathology of circadian rhythm generation
Objective: We investigated whether a transgenic mouse model relevant to AD (APPswe/PS1dE9) exhibits circadian
alterations in locomotor activity in their home cage and whether expression of clock genes involved in
the regulation of the circadian cycle is abnormal in the hippocampus and medulla-pons brain regions isolated
from these mice.
Results: In 2month old female mice the APPswe/PS1dE9 transgene alters levels and patterns in circadian
rhythm of locomotor activity. Expression of the clock genes Per1, Per2, Cry1 and Cry2 was found to increase
at night compared to day in wild-type control mice in the medulla/pons. This effect was blunted for Cry1 and
Cry2 gene expression in APPswe/PS1dE9.
Conclusion: This study suggests altered circadian regulation of locomotor activity is abnormal in female APPswe/
PS1dE9 mice and that this alteration has biomolecular analogies in a widely available model of AD. The
early age at which these effects are manifest suggests that these circadian effects may precede plaque development.
The APPswe/PS1dE9 mouse genetic model may have potential to serve as a tool in understanding the
neuropathology of circadian abnormalities in AD and as a model system to test novel therapeutic agents for
Keywords: Alzheimer's Disease, circadian, clock genes, APPswe/PS1dE9 mice, Per1, Per2, Cry1, Cry2, Bmal, Rev-Erb, Rev-
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