Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis.

Lina Ruan,Kai Du,Jinpeng Lv,Mengjia Tao,Hanbo Pan,Yali Tang,Chunyan Shan,Jianchun Pan,Ruixuan Ye,Meixi Zhang

doi:10.3389/fncel.2019.00432

Abstract

The dysfunction of the hypothalamus–pituitary–adrenal (HPA) axis is often seen in Alzheimer’s disease (AD) patients with cognitive deficits. Selective inhibition of phosphodiesterase (PDE) 4 and 5 has already proven to be effective in reducing beta-amyloid 1–42 (Aβ1–42)-mediated pathology by regulating corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, suggesting that PDE-dependent signaling is involved in Aβ1–42-induced HPA axis dysfunction. However, nausea and vomiting are the side effects of some PDE4 inhibitors, which turn our attention to other PDEs. PDE2 are highly expressed in the hippocampus and cortex, which associate with learning and memory, but not in the area postrema that would cause vomiting. The present study suggested that microinjection of Aβ1–42 to the intracerebroventricle induced learning and memory impairments and dysregulation of the HPA axis by increased expression of CRF and GR. However, the PDE2 inhibitor Bay 60-7550 significantly ameliorated the learning and memory impairment in the Morris water maze (MWM) and step-down passive avoidance tests. The Aβ1–42-induced increased CRF and GR levels were also reversed by the treatment with Bay 60-7550. These Bay 60-7550’s effects were prevented by pretreatment with the PKG inhibitor KT5823. Moreover, the Bay 60-7550-induced downstream phosphorylation of cyclic AMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) expression was also prevented (or partially prevented) by KT5823 or the PKA inhibitor H89. These results may lead to the discovery of novel strategies for the treatment of age-related cognitive disorders, such as AD, which affects approximately 44 million people worldwide.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of beta-amyloid peptides (Aβ), neurofibrillary tangles in the brain, widespread cortical neuronal loss, and progressive memory impairment
Our previous studies suggested that the phosphodiesterase 4 (PDE4) inhibitor rolipram reversed Aβ1– 42-induced memory impairment, as evidenced by increased crossing numbers and shorter latency to reach the target zone where the platform was removed in the test session (Xu et al, 2018)
These outcomes were supported by the subsequent step-down passive avoidance test, which indicated that shortterm (1 h) and long-term (3 h) aversive memory retention was ameliorated by treatment with Bay 60-7550

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of beta-amyloid peptides (Aβ), neurofibrillary tangles in the brain, widespread cortical neuronal loss, and progressive memory impairment. In an acute animal model of AD, microinjection of an oligomeric solution of a Aβ fragment (oAβ) into cerebroventricle (i.c.v.) of animals induces multiple signs of neurodegeneration, which suggests a clear parallel with numerous relevant symptoms of AD patients (Zussy et al, 2011, 2013; Wang et al, 2012; Pineau et al, 2016) This Aβ fragment originates from the proteolysis of parent amyloid proteins (Kubo et al, 2002; Gruden et al, 2007), which initiates a strong and long-lasting activation of the HPA axis, leading to cognitive and learning and memory impairment. Phosphodiesterase 4 (PDE4) inhibitor rolipram reversed this memory deficit through regulation of CRF and GR expression, suggesting that PDEdependent signaling is involved in Aβ1–42-induced HPA axis dysfunction (Xu et al, 2013, 2015)

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Results

Conclusion