title: Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics.
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.
authors: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, United States. robert.s.bitner@abbott.com
authors: R
authors: R
authors: Scott Bitner
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D054828:Histamine H3 Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D018100:Receptors, Histamine H3 / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D054828:Histamine H3 Antagonists; D018722:Nicotinic Agonists; D018100:Receptors, Histamine H3; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1