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

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 stag...

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Published in:The journal of clinical endocrinology and metabolism 2003-12, Vol.88 (12), p.5898-5906
Main Authors: Wu, Ying-Hui, Feenstra, Matthijs G. P, Zhou, Jiang-Ning, Liu, Rong-Yu, Toranõ, Javier Sastre, Van Kan, Hendrikus J. M, Fischer, David F, Ravid, Rivka, Swaab, Dick F
Format: Article
Language:English
Subjects:
Aged
Alzheimer Disease - cerebrospinal fluid
Alzheimer Disease - metabolism
Alzheimer Disease - physiopathology
Biological and medical sciences
Case-Control Studies
Circadian Rhythm
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dopamine - metabolism
Humans
Hydroxyindoleacetic Acid - metabolism
Medical sciences
Melatonin - biosynthesis
Melatonin - cerebrospinal fluid
Melatonin - metabolism
Monoamine Oxidase - genetics
Neurology
Norepinephrine - metabolism
Pineal Gland - metabolism
Receptors, Adrenergic, beta-1 - genetics
RNA, Messenger - metabolism
Serotonin - metabolism
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Summary: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 β1-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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2003-030833