Transforming growth factor-beta inhibits the expression of clock genes

• Published in: Annals of the New York Academy of Sciences 2012-07, Vol.1261 (1), p.79-87
• Main Authors: Gast, Heidemarie, Gordic, Sonja, Petrzilka, Saskia, Lopez, Martin, Müller, Andreas, Gietl, Anton, Hock, Christoph, Birchler, Thomas, Fontana, Adriano
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - physiopathology; Alzheimer's disease; Animals; Basic-Leucine Zipper Transcription Factors - antagonists & inhibitors; Basic-Leucine Zipper Transcription Factors - genetics; Binding; Biological clocks; Circadian rhythm; Circadian Rhythm - genetics; CLOCK Proteins - antagonists & inhibitors; CLOCK Proteins - genetics; Clocks; Cognitive Dysfunction - metabolism; Cytokines; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; E-box; Female; Gene expression; Gene Expression Regulation; Genes; Growth factors; Humans; Impairment; Male; memory; Mice; Middle Aged; Neurons - metabolism; Neurons - pathology; Nuclear Receptor Subfamily 1, Group D, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Patients; Period Circadian Proteins - antagonists & inhibitors; Period Circadian Proteins - genetics; Rhythm; sleep deprivation; Sleep Disorders, Circadian Rhythm - genetics; Sleep Disorders, Circadian Rhythm - physiopathology; sleep genes; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transforming Growth Factor beta2 - cerebrospinal fluid; Transforming Growth Factor beta2 - metabolism
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/j.1749-6632.2012.06640.x

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.