A selective phosphodiesterase 4D inhibitor BPN14770 reverses beta amyloid‐induced memory impairment in humanized PDE4D mice

Abstract

Beta amyloid peptides (Aβ) are known risk factors involved in cognitive impairment in Alzheimer's disease (AD). Type 4 phosphodiesterase (PDE4) inhibitors such as rolipram could upregulate intracellular cAMP level, which further activate downstream target cAMP‐responsive‐ element‐binding protein (CREB), brain‐derived neurotrophic factor (BDNF) and nerve growth factor (VGF) signaling. Although conventional PDE4 inhibitors have benefits on memory enhancement in preclinical and clinical studies, they were prevented to be developed as a novel class of memory‐enhancing drugs due to their adverse effects such as GI irritation. BPN14770, a novel allosteric inhibitor of PDE4D, exhibits high selectivity on PDE4D based on its close interaction with a single amino acid present at primate PDE4D. The present study used the humanized PDE4D (hPDE4D) mice, which provide a unique and powerful genetic tool for assessing the PDE4D target engagement, to investigate the effects of BPN14770 on memory impairment induced by Ab1‐42. Results suggested that BPN14770‐treated mice exhibited significant learning and memory enhancement, as shown in Morris water maze and Y maze tests. The morphological analyses suggested that both the number of dendrites and the total length were significantly increased after treatment hPDE4D mice with BPN14770 for two weeks. The subsequent neurochemical assay indicated that neuroprotective proteins such as pCREB, BDNF and VGF in Ab‐treated hPDE4D mice were upregulated after treatment with BPN14770. These findings provide evidence that BPN14770 may be a potential therapeutic drug for treating cognitive deficits in Alzheimer's disease and its underlying mechanism may be involved in the cAMP‐pCREB‐BDNF/VGF signaling.Support or Funding InformationThis project was supported by R44 MH091791 to Drs. Mark Gurney and Ying Xu.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.