Figure 7
A hypothetical model for the reciprocal control of the hippocampal oscillator.
Orexin signaling and AD-risk genes. (1) and (3) A self-sustained circadian oscillator exists in the hippocampus; (3) and (S1) Orexin signaling can speed up hippocampal oscillation, acting as an input signal to the hippocampal clock; (2) The hippocampal oscillator controls the expression of core clock genes; (4) Several key AD-risk genes, (5) including Bace1/2, which are regulated through D-boxes and E-boxes, respectively; (6) The rhythmicity of Bace2 and ApoE are altered in the hippocampus of APP/PS1dE9 mice; (6) and (S2) The orexin precursor gene is rhythmic in the brain. Thus, our model supports the following notions: Orexin signaling influences hippocampal oscillation; the hippocampal oscillator controls the rhythmic expression of AD-risk genes like Bace1, Bace2, and ApoE, which are the key genes in the metabolism of Aβ; the rhythmicity of these AD-risk genes indicate that disrupted circadian oscillation and sleep both contribute to the risk of AD; and, finally, orexin signaling is involved in reciprocal control of the core clock feedback loop and AD. The blue arrows show the pathways or physiological processes involved in the present study; the black arrows show the well-known pathways or physiological processes; the dashed black arrows represent uncertain relationships between the pathways or physiological processes.
