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.

Highlights

  • Alzheimer's disease (AD) is the most common cause of dementia worldwide and currently affects more than 6% of the population over the age of 65 [1,2]

  • According to this view, decreased levels of brain-derived neurotrophic factor (BDNF) could contribute to the neurite atrophy and synaptic loss observed in the brains of AD patients, and up-regulation of BDNF could control the progression of AD and cognitive decline [29,30]

  • The results of the present study provide direct support for this neurotrophic factor hypothesis, demonstrating that the infusion of BDNF into the hippocampus reverses the learning deficits in the Aβ1-42-induced AD rat model

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Summary

Introduction

Alzheimer's disease (AD) is the most common cause of dementia worldwide and currently affects more than 6% of the population over the age of 65 [1,2]. Among the most robust pathologies observed in AD are the accumulation and deposition of senile plaques composed of amyloid-β peptides (Aβ) in the brain. Aβ is derived from amyloid precursor protein (APP) by β- and γ-secretase, producing 40–42 amino acid Aβ peptides; these plaques can PLOS ONE | DOI:10.1371/journal.pone.0122415. BDNF Ameliorates Learning Deficits in Alzheimer's Disease Aβ is derived from amyloid precursor protein (APP) by β- and γ-secretase, producing 40–42 amino acid Aβ peptides; these plaques can PLOS ONE | DOI:10.1371/journal.pone.0122415 April 7, 2015

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