Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline

Abstract

It is well known that alongside senescence there is a gradual decline in cognitive ability, most noticeably certain kinds of memory such as working, episodic, spatial, and long term memory. However, until recently, not much has been known regarding the specific mechanisms responsible for the decline in cognitive ability with age. Over the past decades, researchers have become more interested in cAMP signaling, and its downstream transcription factor cAMP response element binding protein (CREB) in the context of senescence. However, there is still a lack of understanding on what ultimately causes the cognitive deficits observed with senescence. This review will focus on the changes in intracellular signaling in the brain, more specifically, alterations in cAMP/CREB signaling in aging. In addition, the downstream effects of altered cAMP signaling on cognitive ability with age will be further discussed. Overall, understanding the senescent-related changes that occur in cAMP/CREB signaling could be important for the development of novel drug targets for both healthy aging, and pathological aging such as Alzheimer's disease.

Fig. 1

Simplified schematic of the cAMP/CREB signaling pathway. Multiple pathways are capable of converging to phosphorylate CREB and initiate gene transcription. For standard G-protein coupled receptor signaling (GPCR), binding of a ligand such as norepinephrine (NE) or acetylcholine (ACh) to its receptor activates the α-subunit, which then in turn activates adenylyl cyclase (AC). AC catalyzes the formation of cAMP from ATP in an energy dependent manner. Cyclic AMP activates protein kinase A (PKA) by binding to the regulatory subunits and relieving auto-inhibition. Once activated, the catalytic units of PKA are free to phosphorylate cAMP response-element binding-protein (CREB) in the nucleus. Once phosphorylated CREB binds cAMP response element (CRE) promoter sites on the DNA. CREB then recruits several co-activator proteins (CBP, p300) that have histone-acetyl-transferase activity which loosen the DNA, allowing RNA polymerase II to initiate gene transcription for products such as brain-derived neurotrophic-factor (BDNF) and certain receptor subunits. Phosphodiesterases (PDEs) hydrolyze cAMP and thus attenuate the effects of cAMP downstream. Glutamatergic signaling is also capable of activating the cAMP pathway through AMPA and NMDA receptors. Once the NMDA receptor is activated by AMPA induced depolarization, binding of glutamate, and expulsion of the magnesium ion, calcium flow through the NMDA receptor is capable of activating certain AC isoforms sensitive to calcium (I, III, VIII) which results in subsequent phosphorylation of CREB. In addition, CREB can also experience glutamatergic- and calcium-mediated phosphorylation via the Calmodulin-CamKIV pathway. Lastly, CREB is also capable of being phosphorylated via the mitogen-activated protein-kinase (MAPK) pathway which can be activated by binding of a trophic factor such as BDNF to its receptor tyrosine kinase b (TrkB). Abbreviations : Glutamate (Glu), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor, depolarization (depol.), rat-sarcoma protein (RAS), ribosomal s6 kinase (RS6), RNA polymerase II (RNA Pol II), CREB binding protein (CBP).