Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

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

Molecular mechanisms of cognitive dysfunction following traumatic brain injury

Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration

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

<p>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.</p

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

<p>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. * <i>P</i><0.05.</p

Experiment 1: repeated Abeta injection.

<p>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 “<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029940#s4" target="_blank">Materials and Methods</a>: 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. * <i>P</i><0.05.</p

Natural Abeta oligomer solution and injection.

<p>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 “<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029940#s4" target="_blank">Materials and Methods</a>” 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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029940#pone.0029940-Lein1" target="_blank">[38]</a>. The tip of the guide cannula stopped just above the corpus callosum. The tip of the injection cannula extended into the lateral ventricle.</p

Reversible antisense inhibition of Shaker-like Kv1.1 potassium channel expression impairs associative memory in mouse and rat

Long-term memory is thought to be subserved by functional remodeling of neuronal circuits. Changes in the weights of existing synapses in networks might depend on voltage-gated potassium currents. We therefore studied the physiological role of potassium channels in memory, concentrating on the Shaker-like Kv1.1, a late rectifying potassium channel that is highly localized within dendrites of hippocampal CA3 pyramidal and dentate gyrus granular cells. Repeated intracerebroventricular injection of antisense oligodeoxyribonucleotide to Kv1.1 reduces expression of its particular intracellular mRNA target, decreases late rectifying K(+) current(s) in dentate granule cells, and impairs memory but not other motor or sensory behaviors, in two different learning paradigms, mouse passive avoidance and rat spatial memory. The latter, hippocampal-dependent memory loss occurred in the absence of long-term potentiation changes recorded both from the dentate gyrus or CA1. The specificity of the reversible antisense targeting of mRNA in adult animal brains may avoid irreversible developmental and genetic background effects that accompany transgenic “knockouts”

GGA3KO mice display deficits in GABAergic tonic current.

<p>Recordings were made from DGGCs in hippocampal slices from 6–8 week-old GGA3WT and GGA3KO mice in the presence of 1μM GABA. Tonic current was determined by measuring the difference in holding current amplitude before and after applying 100 μM picrotoxin (PTX). GGA3KO mice exhibited a significant reduction in tonic current amplitude (A). The graph represents mean ± SEM of current amplitude and density (B). * = significantly different to control (p<0.05; <i>t</i>-test, n = 7–8 cells, from 3 animal for genotype).</p