BPN-14770 Ameliorates Memory and Cognitive Impairments by Regulation of Dynamics in A-beta Production and Clearance

Shivani Avasthi

Amyloid beta plaques in the brain.

Amyloid beta plaques in the brain.

Undergraduate Student Project

Introduction

Alzheimer's disease is a neurodegenerative disease that affects our elderly population. In this study, a novel perspective drug BPN-14770 was given to mice. The mice were then put through a series of behavioral tests such as a novel object recognition test and the Morris water maze, to see if the novel substance helped the condition. After the behavioral tests' images were taken to study amyloid beta production. Since the presence of this is indicative of disease, it was used to determine how increasing doses of BPN-14770 affected disease and to see if it was a promising treatment option.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that involves progressive loss of cognitive and memory function due to the accumulation of A-beta plaques . BPN 14770 is an allosteric inhibitor of PDE4D that has beneficial effects on cognition in preclinical and clinical studies. Our previous study suggested that the efficacy of BPN 14770 was 100-fold more potent for improving memory in the humanized PDE4D mice (e.g. knocking a primate-specific N-terminal region in mice) than those of wild-type littermates. However, BPN 14770 exhibited low potency in a mouse surrogate model for vomiting and emesis, which gives it better potential to be a new memory enhancer. In the present study, the Novel object recognition (NOR), Morris Water Maze (MWM), and the step-down passive avoidance tests (PA) were used to test BPN14770's effect on cognitive and memory performance in humanized PDE4D mice crossed with APP/PS1 mice. The results suggested that there was a significant increase in discrimination index in the APP/PS1 x hPDE4D mice treated with BPN 14770 as compared to the wild type. Moreover, there was a significant decrease in the mean latency to platform and increase in crossing number in the target quadrant In the MWM test. Meanwhile,  a significantly longer latency to jump off the platform was found after treatment with BPN14770 in APP/PS1 x hPDE4D mice, supporting the memory enhancing effects of BPN 14770. The subsequent study suggested that BPN14770 decreased A-beta plaques significantly through a decrease in A-beta production and an increase in clearance of A-beta plaques. Importantly, these effects were reversed by pretreatment with either PKA inhibitor H89 or PKG inhibitor KT5823. This finding suggests that BPN14770 could enhance memory by regulation of dynamics in A-beta production and clearance through PKA/PKG-dependent pathway.

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