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Front. Aging Neurosci. | doi: 10.3389/fnagi.2018.00204

Inhibition of phosphodiesterase-4 reverses Aβ-induced memory impairment by regulation of HPA axis related cAMP signaling

 Ying Xu1, 2, Naping Zhu1, Wen Xu1, Han Ye1, Kaiping Liu1, Feiyan Wu1, Meixi Zhang3,  Yun Ding4, Cong Zhang2, James O'Donnell2,  Hanting Zhang5 and  Jianchun Pan1*
  • 1School of Pharmacy, Wenzhou Medical University, China
  • 2Pharmacology, University at Buffalo, United States
  • 3Pingyang Hospital of Traditional Chinese Medicine, China
  • 4Hangzhou Geriatric Hospital, China
  • 5Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University, United States

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.

Keywords: Alzheimer's disease, Aβ 1-42, Rolipram, learning and memory, Phosphodiesterases 4A, HPA axis

Received: 21 May 2018; Accepted: 14 Jun 2018.

Edited by:

CHENG-XIN GONG, Institute for Basic Research in Developmental Disabilities (IBR), United States

Reviewed by:

Junqing Yang, Chongqing Medical University, China
Tun Li, University of California, San Francisco, United States  

Copyright: © 2018 Xu, Zhu, Xu, Ye, Liu, Wu, Zhang, Ding, Zhang, O'Donnell, Zhang 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 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.

* Correspondence: Prof. Jianchun Pan, Wenzhou Medical University, School of Pharmacy, Wenzhou, China, wenzhoupan2003@163.com