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Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the "master clock"

Ying-Hui Wu^*, David F. Fischer^*,1, Andries Kalsbeek^*, Marie-Laure Garidou-Boof^*, Jan van der Vliet^*, Caroline van Heijningen^*, Rong-Yu Liu, Jiang-Ning Zhou and Dick F. Swaab^*,2

^* Netherlands Institute for Neuroscience, Amsterdam, The Netherlands;

Anhui Geriatrics Institute, The first Affiliated Hospital of Anhui Medical University, Hefei, P. R. China; and

Department of Neurobiology, School of Life Science, University of Science and Technology of China, Hefei, P.R. China

²Correspondence: Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. E-mail: d.f.swaab{at}nin.knaw.nl

ABSTRACT

The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer’s disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hß1-adrenergic receptor (hß1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hß1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.—Wu, Y-H., Fischer, D. F., Kalsbeek, A., Garidou-Boof, M-L., van der Vliet, J., van Heijningen, C., Liu, R-Y., Zhou, J-N., Swaab, D. F. Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the "master clock."

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