A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway.

Yulu Wang,Hanting Zhang,Min Ma,James M O’Donnell,Shichen Shen,Mark E Gurney,Shichao Gao,Ling Chen,Ying Xu,Victor Zheng,Jun Qu

doi:10.3389/fcell.2020.599389

Abstract

A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders.

Highlights

Alzheimer’s disease (AD) is characterized by progressive decline in learning and memory with accompanying neuropathological changes
We show that scopolamine-impairment reduces the ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) in hippocampus and that this too is reversed by BPN14770
A global, quantitative proteomics/systems-biology analysis showed that inhibition of PDE4D differentially regulated cellular pathways in brain regions associated with memory such as the hippocampus and frontal cortex as shown in the flow chart for the study (Figure 1)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by progressive decline in learning and memory with accompanying neuropathological changes. It has been possible to design allosteric inhibitors that display PDE4 subtype selectivity, in the case of phosphodiesterase-4D (PDE4D), the allosteric binding site is unique to primates, and humans (Burgin et al, 2010). A single amino acid difference in UCR2, a phenylalanine in PDE4D and a tyrosine in PDE4A, B, and C, has allowed the design of PDE4D subtype-selective allosteric inhibitors. Based on the unique binding pose of BPN14770 to primate PDE4D, we humanized the mouse PDE4D gene by knocking into C57bl/6 mouse embryonic stem cells a single-nucleotide substitution that replaces UCR2 tyrosine 271 by phenylalanine. Mutation of the allosteric site increases the potency and selectivity of BPN14770 in the humanized PDE4D mice as compared to wild-type (WT) littermates

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Conclusion