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School of Pharmacy


Pharmaceutical Sciences


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.

Source Citation

Xu Y, Zhu N, Xu W, Ye H, Liu K, Wu F, Zhang M, Ding Y, Zhang C, Zhang H, O’Donnell J and Pan J (2018) Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling. Front. Aging Neurosci. 10:204. doi: 10.3389/fnagi.2018.00204


Copyright © 2018 Xu, Zhu, Xu, Ye, Liu, Wu, Zhang, Ding, Zhang, Zhang, O’Donnell and Pan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.



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