Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics

Biochem Pharmacol. 2012 Mar 15;83(6):705-14. doi: 10.1016/j.bcp.2011.11.009. Epub 2011 Nov 19.

Abstract

CREB-mediated transcription can be initiated by membrane receptor stimulation and subsequent activation of intracellular pathways to the cell nucleus, and has been described as a molecular switch required for learning and memory. While CREB dimers are thought to be constitutively bound to response elements on DNA under basal conditions, it is CREB phosphorylation that is believed to be responsible for transcriptional activation leading to gene products such as BDNF that play a key role in synaptic plasticity and cognitive function. Conversely, preclinical and clinical findings now suggest that impaired CREB phosphorylation may be a pathological component in neurodegenerative disorders, in particular Alzheimer's disease (AD). In this regard, pharmacological-induced CREB phosphorylation in brain regions associated with cognition, i.e. cortex and hippocampus may represent a mechanistic basis for the development of novel AD therapeutics. The purpose of this commentary is to describe an experimental strategy to biochemically characterize the pharmacological induction of CREB phosphorylation as a mechanistic marker across different pharmacological classes of compounds for the potential treatment of AD that include: α7 nicotinic agonists, H3 antagonists and 11β HSD1 inhibitors.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Biomarkers / metabolism
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / physiopathology
  • Cognition / drug effects
  • Cognition / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Histamine H3 Antagonists / pharmacology
  • Histamine H3 Antagonists / therapeutic use*
  • Humans
  • Memory / drug effects*
  • Memory / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Neurons / metabolism
  • Nicotinic Agonists / pharmacology
  • Nicotinic Agonists / therapeutic use*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Inbred F344
  • Receptors, Histamine H3 / metabolism
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • Chrna7 protein, human
  • Chrna7 protein, mouse
  • Chrna7 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Histamine H3 Antagonists
  • Nicotinic Agonists
  • Receptors, Histamine H3
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1