title: Transforming growth factor-beta inhibits the expression of clock genes.
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.
authors: Department of Neurology, Inselspital, University Hospital Berne, University of Berne, Berne, Switzerland.
authors: Heidemarie
authors: H
authors: Gast
authors: Sonja
authors: S
authors: Gordic
authors: Saskia
authors: S
authors: Petrzilka
authors: Martin
authors: M
authors: Lopez
authors: Andreas
authors: A
authors: Müller
authors: Anton
authors: A
authors: Gietl
authors: Christoph
authors: C
authors: Hock
authors: Thomas
authors: T
authors: Birchler
authors: Adriano
authors: A
authors: Fontana
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D056926:CLOCK Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D020178:Sleep Disorders, Circadian Rhythm / Q000235:genetics / Q000503:physiopathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C063898:DBP protein, human; D004268:DNA-Binding Proteins; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539022:PER1 protein, human; C421902:PER2 protein, human; D056950:Period Circadian Proteins; C489490:TEF protein, human; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2; D056926:CLOCK Proteins