Brain-derived neurotrophic factor ameliorates learning deficits in a rat model of Alzheimer's disease induced by aβ1-42

Abstract

An emerging body of data suggests that the early onset of Alzheimer's disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.

Fig 1. Effect of intracerebroventricular injection of Aβ1–42 aggregates on spatial learning memory in the Morris water-maze test.

(A) The experimental protocol. (B) Representative swim traces of each group in the fifth training trial. (C) Escape latency and (D) swimming speed in each training trial were also analyzed. (E) The time spent in the target quadrant in the probe task. (F) The number of times crossing the platform in the probe task. (G) The total distance traveled in the open field test after the probe task. (H) The expression of BDNF, NGF and NT-3 protein in hippocampus in the sham and Aβ1–42 aggregate-treated rats. n = 8 each group. * P < 0.05 and ** P < 0.01 compared with sham controls.

Fig 2. Effect of intra-hippocampal injections of BDNF (0.05, 0.25 and 1.0 μg/side), NGF (0.25 μg/side) and NT-3 (0.25 μg/side) on spatial learning function in the Aβ1-42-treated rat model of Alzheimer's disease.

(A) Representative swim traces of each group in the fifth training trial. (B) Escape latency and (C) swimming speed in each training trial were also analyzed. (D) The time spent in the target quadrant in the probe task. (E) The number of times crossing the platform in the probe task. (F) The total distance traveled in the open field test after the probe task. n = 8/group. For panel B, * P < 0.05, ** P < 0.01, Aβ1–42 + saline vs sham control group; # P < 0.05, Aβ1–42 + NGF vs sham control group; § P < 0.05, Aβ1–42 + NT-3 vs sham control group. For the other panels, * P < 0.05, ** P < 0.01, and *** P < 0.0001, compared with sham controls. # P <0.05 as compared with Aβ1–42 + saline group.

Fig 3. Effect of intra-hippocampal injections of BDNF (1.0 μg), NGF (0.25 μg), and NT-3 (0.25 μg) on MAPK expression in the hippocampus in a rat model of Alzheimer's disease.

(A) representative western blots of each group. GAPDH was used as the internal loading control. (B) relative expression of phosphorylated ERK. (C) and (D) relative expression of phosphorylated JNK and p38. * P < 0.05, ** P < 0.01, and *** P < 0.0001 compared with sham controls. # P <0.05 as compared with Aβ1–42 + saline group.

Fig 4. Effect of intra-hippocampal injections of BDNF, ERK activator ceramide C6 and the ERK inhibitor PD98059 on spatial learning function in the rat model of Alzheimer's disease.

(A) Representative swim traces of each group in the fifth training trial. (B) Escape latency and (C) swimming speed in each training trial were also analyzed. (D) The time spent in the target quadrant in the probe task. (E) The number of times crossing the platform in the probe task. (F) The total distance traveled in the open field test after the probe task. n = 8 each group. For panel B, * P < 0.05, ** P < 0.01, Aβ1–42 + PD98059 + BDNF vs Aβ1–42 + BDNF group; # P< 0.05, Aβ1–42 + ceramide C6 vs. Aβ1–42 + BDNF group. For the other panels, * P < 0.05 and *** P < 0.0001 compared with the Aβ1–42 + BDNF group.