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

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

Synaptic therapy in Alzheimer's disease: a CREB-centric approach.

Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription)

HISTONE ACETYLTRANSFERASE ACTIVATORS AND COMPOSITIONS AND USES THEREOF

The invention provides pharmaceutical compositions and methods for treating cancer, neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein by administering a HAT modulator and a HDAC modulator to a subject

HISTONE ACETYLTRANSFERASE ACTIVATORS AND USES THEREOF

The invention provides compounds and compositions comprising compounds that modulate histone acyl transferase (HAT). The invention further provides methods for treating neurodegenerative disorders, conditions associated with accumulated amyloid-beta peptide deposits, Tau protein levels, and/or accumulations of alpha-synuclein as well as cancer by administering a compound that modulates HAT to a subject

Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Background Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown. Methods This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation. Results Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau. Conclusions Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions

Identification of a Novel 1,2,3,4-Tetrahydrobenzo[<i>b</i>][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer’s Disease

Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of the cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported potent quinoline-based PDE5 inhibitors (PDE5Is) for the treatment of Alzheimer’s disease (AD). However, the low aqueous solubility rendered them undesirable drug candidates. Here we report a series of novel PDE5Is with two new scaffolds, 1,2,3,4-tetrahydrobenzo­[<i>b</i>]­[1,6]­naphthyridine and 2,3-dihydro-1<i>H</i>-pyrrolo­[3,4-<i>b</i>]­quinolin-1-one. Among them, compound <b>6c</b>, 2-acetyl-10-((3-chloro-4-methoxybenzyl)­amino)-1,2,3,4-tetrahydrobenzo­[<i>b</i>]­[1,6]­naphthyridine-8-carbonitrile, the most potent compound, has an excellent in vitro IC₅₀ (0.056 nM) and improved aqueous solubility as well as good efficacy in a mouse model of AD. Furthermore, we are proposing two plausible binding modes obtained through in silico docking, which provide insights into the structural basis of the activity of the two series of compounds reported herein