Transforming growth factor-beta inhibits the expression of clock genes

Ann N Y Acad Sci. 2012 Jul:1261:79-87. doi: 10.1111/j.1749-6632.2012.06640.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / physiopathology*
  • Animals
  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic-Leucine Zipper Transcription Factors / genetics
  • CLOCK Proteins / antagonists & inhibitors
  • CLOCK Proteins / genetics
  • Circadian Rhythm / genetics*
  • Cognitive Dysfunction / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Expression Regulation*
  • Humans
  • Male
  • 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
  • Period Circadian Proteins / antagonists & inhibitors
  • Period Circadian Proteins / genetics
  • Sleep Disorders, Circadian Rhythm / genetics
  • Sleep Disorders, Circadian Rhythm / physiopathology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transforming Growth Factor beta2 / cerebrospinal fluid
  • Transforming Growth Factor beta2 / metabolism*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • DBP protein, human
  • DNA-Binding Proteins
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • PER1 protein, human
  • PER2 protein, human
  • Period Circadian Proteins
  • TEF protein, human
  • Transcription Factors
  • Transforming Growth Factor beta2
  • CLOCK Proteins