BAY 73-6691 Alters Neuron Plasticity and Phosphorylation of Tau Through Regulation of Cyclic Guanosine Monophosphate/Protein Kinase G/Cyclic Adenosine Monophosphate Response Element-Binding Protein Pathway

Alzheimer's disease (AD) is one of neurodegenerative diseases characterized by cognitive and memory decline, accompanying with neurofibrillary tangles (NFTs) made of hyperphosphorylated tau protein and senile plaques (SP) accumulated by beta-amyloid protein (A beta). BAY 73-6691, an inhibitor of phosphodiesterase-9 (PDE-9), can improve learning and memory of elderly rats. However, the effects of BAY 73-6691 on neuroapoptotic and neuroinflammatory events, as well as synaptic plasticity of differentiated PC12 cells are remain unclear. In this work, we screened apoptotic cells induced by A beta(25-35) via flow cytometry. TNF-alpha, IL-1 beta, IL-6 secreted by PC12 cells were estimated by ELISA kits. The levels of cGMP, PKG and CREB mediated by BAY 73-6691 were assessed. Moreover, we conducted western blots analysis to evaluate the phosphorylation of tau and synaptic related proteins. Results showed that BAY 73-6691 could reduce A beta(25-35)-triggered neuroapoptosis and neuroinflammation. Phosphorylation of tau was inhibited by BAY 73-6691, whereas sildenafil citrate (SC, an inhibitor of cGMP) partially weakened the effect of BAY 73-6691. Additionally, synaptic plasticity restored by BAY 73-6691 was also suppressed via SC. Taken together, BAY 73-6691 exhibited neuroprotective effects, and altered tau phosphorylation as well as synaptic related proteins through cGMP/PKG/CREB pathway.