Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of senile dementia. Recently, scientists have put significant effort into exploring the molecular mechanisms involved in the pathological processes leading to the disease. A vast number of studies have focused on understanding the nitric oxide (NO) signaling pathway, which culminates with the phosphorylation of the transcription factor cAMP-responsive element-binding protein (CREB) through the increase of the second messenger cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase. This book chapter provides an overview of the progress being made in modulating the hippocampal synaptic transmissions, which are critical for learning and memory, by targeting the different components of the NO/cGMP/CREB phosphorylation signaling pathway. Furthermore, a description of recent research on this pathway through the use of phosphodiesterase inhibitors is emphasized.

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

“…In the hippocampus during long-term potentiation and in other neural tissues, both the cGMP/PKG and the cAMP/PKA pathways contribute to CREB phosphorylation [85][86][87][88][89][90], and PKA-mediated CREB phosphorylation promotes PGC1␣ transcription [67], so cGMP/PKG/CREB signaling might promote PGC1␣ expression as well. In addition, cGMP may contribute to the post-translational regulation of PGC1␣.…”

“…Furthermore, sildenafil improves insulin sensitivity and endothelial inflammation in patients [124][125][126], so sildenafil might also promote insulin sensitivity and suppress inflammation in AD brains. Since cGMP/PKG signaling mediates long-term potentiation via CREB phosphorylation [85][86][87][88][89][90]117], sildenafil should improve the learning and memory impairments associated with AD. Therefore, in theory, most doses of sildenafil should improve multiple hallmarks of AD, including excessive A␤ generation, impaired mitochondrial biogenesis, oxidative stress, neuroinflammation, hypoperfusion, insulin resistance, neuron loss, insufficient neurogenesis, and memory deficits.…”

Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer’s disease

“…Specific phosphodiesterase (PDE) inhibitors have been shown to improve memory function in a variety of animal models of AD. PDE inhibitors stimulate gene transcription by activating the CREB ( Fiorito et al, 2018 ; Figure 3 ). Long-term memory formation and persistent long-term potentiation (LTP) measuring the synaptic plasticity and strength, are driven by CREB-dependent gene expression ( Davis et al, 2000 ).…”

Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale

“…Both cAMP/PKA and cGMP/PKG signaling activate CREB by phosphorylating it at Ser133 [74][75][76][77][78][79]. pSer133-CREB protein levels are decreased in the AD hippocampus [80], the AD prefrontal cortex, and AD peripheral blood mononuclear cells [81].…”

“…Both cAMP/PKA and cGMP/PKG signaling promote mitochondrial biogenesis and antioxidant gene expression via CREB-and SIRT1-mediated PGC1␣ activation [92][93][94][95][96][97][98][99][100][101][102][103][104][105]. In addition to activating CREB [74][75][76][77][78][79], which induces PGC1␣ transcription [83,91], both cAMP/PKA and cGMP/PKG signaling activate SIRT1 [94-96, 98, 104-110]. SIRT1 exerts multiple beneficial effects in AD, including downregulating pro-amyloidogenic ␤-secretase (BACE1) and upregulating anti-amyloidogenic A Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) [106], as well as deacetylating and thereby post-translationally activating PGC1␣ [97,[111][112][113][114][115][116][117][118].…”