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

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 10 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2018.00204

DOI=10.3389/fnagi.2018.00204

ISSN=1663-4365

ABSTRACT=Beta amyloid peptides (Aβ) is found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in Alzheimer’s disease (AD) patients. 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 Aβ 1-42-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), two months (2 M) and six months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ 1-42. 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 Aβ 1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor and glucocorticoid receptors (CRF-R and GR) levels; while 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 Aβ 1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.