Nitric oxide/cGMP/CREB pathway and amyloid-beta crosstalk: From physiology to Alzheimer's disease

The nitric oxide (NO)/cGMP pathway has been extensively studied for its pivotal role in synaptic plasticity and memory processes, resulting in an increase of cAMP response element-binding (CREB) phosphorylation, and consequent synthesis of plasticity-related proteins. The NO/cGMP/CREB signaling is downregulated during aging and neurodegenerative disorders and is affected by Amyloid-beta peptide (A beta) and tau protein, whose increase and deposition is considered the key pathogenic event of Alzheimer's disease (AD). On the other hand, in physiological conditions, the crosstalk between the NO/cGMP/PKG/CREB pathway and A beta ensures long-term potentiation and memory formation.This review summarizes the current knowledge on the interaction between the NO/cGMP/PKG/CREB pathway and A beta in the healthy and diseased brain, offering a new perspective to shed light on AD pathophysiology. We will focus on the synaptic mechanisms underlying A beta physiological interplay with cGMP pathway and how this balance is corrupted in AD, as high levels of A beta interfere with NO production and cGMP molecular signaling leading to cognitive impairment.Finally, we will discuss results from preclinical and clinical studies proposing the increase of cGMP signaling as a therapeutic strategy in the treatment of AD.