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Molecular Changes Underlying Reduced Pineal Melatonin Levels in Alzheimer Disease: Alterations in Preclinical and Clinical Stages

Anhui Geriatric Institute (Y.-H.W., J.-N.Z., R.-Y.L.), First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui People’s Republic of China; Netherlands Institute for Brain Research (Y.-H.W., M.G.P.F., D.F.F., R.R., D.F.S.), Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Pharmacy (J.S.T., H.J.M.V.K.), Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Jiang-Ning Zhou, M.D., Ph.D., Anhui Geriatric Institute, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui People’s Republic of China. E-mail: anhuigi{at}mail.hf.ah.cn.

A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of ß₁-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.

This work was supported by the China Committee of the Royal Netherlands Academy of Arts and Sciences (01CDP019, 02CDP014), the National Key project for Basic Science of China (G1999054007), the Hersenstichting Nederland, and the Research Institute for Diseases in the Elderly, the Ministry of Education and Science, and the Ministry of Health, Welfare, and Sports through The Netherlands Organization for Scientific Research.

Abbreviations: AD, Alzheimer disease; CSF, cerebrospinal fluid; DA, dopamine; 5-HIAA, 5-hydroxyindoleacetic acid; HIOMT, hydroxyindole-O-methyltransferase; 5-HT, serotonin; HVA, homovanilic acid; MAO, monoamine oxidase; MHPG, 3-methoxy-4-hydroxyphenylglycol; NA, noradrenalin; NAT, N-acetyltransferase; SCN, suprachiasmatic nucleus; TPH, tryptophan hydroxylase; Trp, tryptophan.

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