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

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: alpha 7 nicotinic agonists, H3 antagonists and 11 beta HSD1 inhibitors. (C) 2011 Elsevier Inc. All rights reserved.