Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling.

Ying Xu,Kaiping Liu,Feiyan Wu,Jiangchun Pan,Meixi Zhang,Hanting Zhang,Chong Zhang,Han Ye,Naping Zhu,James O'Donnell,Yun Ding,Wen Xu

doi:10.3389/fnagi.2018.00204

Abstract

Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.

Highlights

Alzheimer’s disease (AD), the most common type of dementia, is a progressive nervous system degenerative disease characterized by subjective cognitive decline (SCD) and mild cognitive impairment (MCI) (Heckman et al, 2015)
The present study suggested that Aβ1-42 intracerebroventricular administration caused overall impairment of learning and memory processes in both of the Morris water-maze (MWM) and passive avoidance (PA) tests at 1 week, 2 and 6 months after treatment, of which the effect was most prominent at 2 months
The subsequent studies demonstrated that the Phosphodiesterase 4 (PDE4) inhibitor rolipram was able to ameliorate Aβ1-42-induced learning and memory impairment by regulating the HPA axis, leading to increases in cAMP-related proteins such as the ratio of pCREB/CREB and brain-derived neurotropic factor (BDNF) expression

Summary

Introduction

Alzheimer’s disease (AD), the most common type of dementia, is a progressive nervous system degenerative disease characterized by subjective cognitive decline (SCD) and mild cognitive impairment (MCI) (Heckman et al, 2015). The amyloid cascade hypothesis has been considered as the central hypothesis for the cause of AD, which suggests that memory deficits correlate closely with cortical soluble beta amyloid (Aβ) oligomers and protofibrils (Blennow et al, 2006). Recent studies suggested that it is not sufficient to decrease the cerebral Aβ levels for the purpose of preventing memory impairment because the accumulation of beta amyloid or senile plaques is often comorbid with increased neurofibrillary tangles (Ballard et al, 2011), making the symptoms irreversible in the later period of the disease. Early intervention with medicine is necessary to counteract the progress of memory deficits and dementia

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