Abstract
Disturbances of sleep-wake rhythms are an important problem in Alzheimer's disease (AD). Circadian rhythms are regulated by clock genes. Transforming growth factor-beta (TGF-β) is overexpressed in neurons in AD and is the only cytokine that is increased in cerebrospinal fluid (CSF). Our data show that TGF-β2 inhibits the expression of the clock genes Period (Per)1, Per2, and Rev-erbα, and of the clock-controlled genes D-site albumin promoter binding protein (Dbp) and thyrotroph embryonic factor (Tef). However, our results showed that TGF-β2 did not alter the expression of brain and muscle Arnt-like protein-1 (Bmal1). The concentrations of TGF-β2 in the CSF of 2 of 16 AD patients and of 1 of 7 patients with mild cognitive impairment were in the dose range required to suppress the expression of clock genes. TGF-β2-induced dysregulation of clock genes may alter neuronal pathways, which may be causally related to abnormal sleep-wake rhythms in AD patients.
© 2012 New York Academy of Sciences.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / cerebrospinal fluid
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Alzheimer Disease / physiopathology*
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Animals
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Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
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Basic-Leucine Zipper Transcription Factors / genetics
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CLOCK Proteins / antagonists & inhibitors
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CLOCK Proteins / genetics
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Circadian Rhythm / genetics*
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Cognitive Dysfunction / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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Female
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Gene Expression Regulation*
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Humans
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Male
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Mice
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Middle Aged
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Neurons / metabolism
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Neurons / pathology
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Nuclear Receptor Subfamily 1, Group D, Member 1 / antagonists & inhibitors
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Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
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Period Circadian Proteins / antagonists & inhibitors
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Period Circadian Proteins / genetics
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Sleep Disorders, Circadian Rhythm / genetics
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Sleep Disorders, Circadian Rhythm / physiopathology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transforming Growth Factor beta2 / cerebrospinal fluid
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Transforming Growth Factor beta2 / metabolism*
Substances
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Basic-Leucine Zipper Transcription Factors
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DBP protein, human
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DNA-Binding Proteins
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NR1D1 protein, human
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Nuclear Receptor Subfamily 1, Group D, Member 1
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PER1 protein, human
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PER2 protein, human
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Period Circadian Proteins
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TEF protein, human
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Transcription Factors
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Transforming Growth Factor beta2
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CLOCK Proteins