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

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.

Keywords: Alzheimer's disease; Aβ1-42; HPA axis; Phosphodiesterases 4A; learning and memory; rolipram.

Figure 1

Aβ1-42 induced spatial memory impairment in the Morris water maze task at 1 week, 2 and 6 months after intracerebroventricular microinjection of Aβ1-42. During the acquisition trials of the water maze task, learning curve were tested after intracerebroventricular microinjection of Aβ1-42 1 week (A), 2 months (B), and 6 months (C). The probe trial was conducted 1 and 24 h after training, the latency to reach the platform (D,F) and the number of platform crossings (E,G) were determined. Values shown are means ± SEM, n = 10; ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001 vs. vehicle-treated control group.

Figure 2

Aβ1-42 induced memory impairment in the step-down passive avoidance test at 1 week, 2 and 6 months after intracerebroventricular microinjection of Aβ1-42. Retention tests were conducted 3 (A) and 24 h (B) after the training session. Values shown are means ± SEM, n = 10; ^*p < 0.05 and ^***p < 0.001 vs. vehicle-treated control group.

Figure 3

The effects of rolipram on Aβ1-42-induced memory impairment in the Morris water-maze test in mice. One and a half months after microinfusion with Aβ1-42 into cerebroventricle, mice were administrated with rolipram for 14 days. H89 and KT5823 were pretreated 30 min before rolipram administration every day. During the acquisition trials of the water maze task, learning curve was tested 24 h after last treatment with rolipram (A,B). The probe trial was conducted 1 and 24 h after training, the latency to reach the platform (C,E) and the number of platform crossings (D,F) were determined. Values shown are means ± SEM, n = 10; ^**p < 0.01 and ^***p < 0.001 vs. vehicle treated sham group. ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 vs. vehicle-treated Aβ group. ^$$P < 0.01 and ^$$$P < 0.001 vs. rolipram (1.0 mg/kg)-treated Aβ group.

Figure 4

The effects of rolipram on 3-h (A) and 24-h (B) memory retention in the step-down passive avoidance test in Aβ42-treated mice. Aβ42-induced decreases in 3-h and 24-h retention were reversed by chronic treatment with rolipram for 14 days Values shown are means ± SEM, n = 10; ^***p < 0.001 vs. vehicle-treated control group. ^###p < 0.001 vs. vehicle-treated Aβ group. ^$$$p < 0.001 vs. rolipram (1.0 mg/kg)-treated Aβ group.

Figure 5

The effects of rolipram on the ratio of adrenal gland weight to body weight (AG/B) (mg/g) (A) and serum corticosterone level (B) in Aβ42-treated mice. Values shown are means ± SEM, n = 10; ^**p < 0.01 and ^***p < 0.001 vs. vehicle-treated control group. ^###p < 0.001 vs. vehicle-treated Aβ group. ^$p < 0.05 vs. rolipram (1.0 mg/kg)-treated Aβ group.

Figure 6

The effects of rolipram on Aβ-induced changes in CRF receptor and GR expression in the hippocampus (A,C) and in the cortex (B,D) of mice. Values shown are means ± SEM, n = 10; ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001 vs. vehicle-treated control group. ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 vs. vehicle-treated Aβ group. ^$$p < 0.01 and ^$$$p < 0.001 vs. rolipram (1.0 mg/kg)-treated Aβ group.

Figure 7

The effects of rolipram on Aβ-induced changes in the ratio of pCREB to CREB and BDNF expression in the hippocampus (A,C) and the cortex (B,D) of mice. Values shown are means ± SEM, n = 10; ^**p < 0.01 and ^***p < 0.001 vs. vehicle-treated control group. ^#p < 0.05, ^##p < 0.01 and ^###p < 0.001 vs. vehicle-treated Aβ group. ^$p < 0.05, ^$$p < ,0.01 and ^$$$p < 0.001 vs. rolipram (0.5 or 1.0 mg/kg)-treated Aβ group.

Figure 8

Molecular mechanisms describe the Aβ-induced vicious circle. Aβ1-42 induces HPA axis hyperactivity and decreases the cAMP level, leading to abnormalities in downstream molecules, i.e., decreased phosphorylation of CREB and BDNF expression, which in turn to deteriorate learning and memory disorders. However, Inhibition of PDE4 increases cAMP level and stimulates HPA axis negative feedback regulation, resulting in decreases in CORT releasing and CRF receptor and GR expression.