Orexin signaling regulates both the hippocampal clock and the circadian oscillation of Alzheimer's disease-risk genes.

Alzheimer's disease (AD) is a circadian clock-related disease. However, it is not very clear whether pre-symptomatic AD leads to circadian disruption or whether malfunction of circadian rhythms exerts influence on development of AD. Here, we report a functional clock that exists in the hippocampus. This oscillator both receives input signals and maintains the cycling of the hippocampal Per2 gene. One of the potential inputs to the oscillator is orexin signaling, which can shorten the hippocampal clock period and thereby regulate the expression of clock-controlled-genes (CCGs). A 24-h time course qPCR analysis followed by a JTK_CYCLE algorithm analysis indicated that a number of AD-risk genes are potential CCGs in the hippocampus. Specifically, we found that Bace1 and Bace2, which are related to the production of the amyloid-beta peptide, are CCGs. BACE1 is inhibited by E4BP4, a repressor of D-box genes, while BACE2 is activated by CLOCK:BMAL1. Finally, we observed alterations in the rhythmic expression patterns of Bace2 and ApoE in the hippocampus of aged APP/PS1dE9 mice. Our results therefore indicate that there is a circadian oscillator in the hippocampus whose oscillation could be regulated by orexins. Hence, orexin signaling regulates both the hippocampal clock and the circadian oscillation of AD-risk genes.