Abstract

Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

Highlights

  • IntroductionIt has been proposed that Alzheimer’s disease (AD) associated memory loss is caused by soluble amyloid-beta (Abeta) oligomers, especially during early stages of AD before significant neuronal cell death has occurred [1,2]

  • Alzheimer’s disease (AD) is characterized by a severe loss of memory function

  • The main conclusion from this study is that natural Abeta oligomers can acutely impair the formation of a contextual fear memory

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Summary

Introduction

It has been proposed that AD associated memory loss is caused by soluble amyloid-beta (Abeta) oligomers, especially during early stages of AD before significant neuronal cell death has occurred [1,2]. This model is supported by a number of observations. In AD mouse models memory loss is observed before the formation of plaques but during and correlating with an increase in Abeta oligomers [5,6,7]. This suggests that, at least during the early stages of AD, memory loss might be reversed by preventing the formation or action of Abeta oligomers

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