Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice - PubMed (original) (raw)

Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice

Kara A Kittelberger et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Natural Abeta oligomer solution and injection.

A) Blot image showing the presence of Abeta monomers, dimers, trimers, and tetramers in the Abeta solution. The 6E10 antibody was used for detection of Abeta oligomers that were removed from the Abeta solution using immunoprecipitation with A/G beads and 4G8 antibody (IP1, IP2, IP3: oligomers bound to beads used for first, second, and third immunoprecipitation). No oligomers were detected after three rounds of immunoprecipitation, which confirmed the absence of Abeta oligomers in the control solution (see “Materials and Methods” for a detailed description of how Abeta and control solutions were generated). B) Diagram showing the location of the guide cannula (green) and the injector cannula (red) in a Nissl-stained coronal section of the mouse brain . The tip of the guide cannula stopped just above the corpus callosum. The tip of the injection cannula extended into the lateral ventricle.

Figure 2

Figure 2. Experiment 1: repeated Abeta injection.

Top) Diagram showing the design of experiment 1. Separate groups of mice were injected three times with either control or Abeta solution. Bottom) Graphs showing average freezing scores during fear conditioning on day 1 and the two retrieval trials on day 2 (see “Materials and Methods: Analysis of freezing behavior” for explanation of intervals on the X axis). Mice injected with the Abeta solution (n = 5) had significantly lower freezing scores during the context fear retrieval trial as compared with mice injected with the control solution (n = 6). Error bars are standard errors of means. * P<0.05.

Figure 3

Figure 3. Experiment 2: single Abeta injection 1 hour before fear conditioning.

Top) Diagram showing the design of experiment 2. Separate groups of mice were injected one time with either control or Abeta solution 1 hour before fear conditioning. Bottom) Graphs showing average freezing scores during fear conditioning on day 1 and the two retrieval trials on day 2. Mice injected with the Abeta solution (n = 8) had significantly lower freezing scores during the context fear retrieval trial as compared with mice injected with the control solution (n = 10). Error bars are standard errors of means. * P<0.05.

Figure 4

Figure 4. Experiment 3: single Abeta injection 2 hours before fear conditioning.

Top) Diagram showing the design of experiment 3. Separate groups of mice were injected one time with either control or Abeta solution 2 hours before fear conditioning. Bottom) Graphs showing average freezing scores during fear conditioning on day 1 and the two retrieval trials on day 2. There was no difference during any of the intervals analyzed between mice injected with the Abeta solution (n = 10) and mice injected with the control solution (n = 8). Error bars are standard errors of means.

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References

    1. Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008;192:106–113. - PMC - PubMed
    1. Krafft GA, Klein WL. ADDLs and the signaling web that leads to Alzheimer's disease. Neuropharmacology. 2010;59:230–242. - PubMed
    1. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580. - PubMed
    1. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999;46:860–866. - PubMed
    1. Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, et al. Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. European Journal of Neuroscience. 2003;17:388–396. - PubMed

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