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

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.

Amyloid‐β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila

“…Disturbances in sleep across many species, including flies, mice, and humans, have been shown to cause cognitive impairment and memory deficits (Graves et al, ; McDermott et al, ; Ganguly‐Fitzgerald et al, ; Abel et al, ; Goel et al, ). Aβ accumulation is also believed to cause cognitive deficits across these species (Iijima et al, ; Lesne et al, , ; Kittelberger et al, ). It has been shown that circadian rhythms are affected by neural expression of Aβ in flies while the molecular clock remains intact (Chen et al, ), suggesting that Aβ may influence other behaviors, such as sleep.…”

Age‐related synaptic dysfunction in Tg2576 mice starts as a failure in early long‐term potentiation which develops into a full abolishment of late long‐term potentiation

“…There is evidence suggesting that Aβ causes an age‐dependent memory decline (Westerman et al, ; Lesné et al, ; Kittelberger et al, ), but the exact mechanisms underlying this cognitive dysfunction remain under debate. Unlike their WT littermates, Tg2576 mice suffer a deterioration of synaptic plasticity with age (Chapman et al, ; Jacobsen et al, ; Mitchell et al, ; Lee et al, ).…”

Hsp90 Chaperone Inhibitor 17-AAG Attenuates Aβ-Induced Synaptic Toxicity and Memory Impairment

“…The experiments were conducted with conditioned freezing chambers (Coulbourn Instruments) following a similar protocol recently published (Kittelberger et al, 2012). Wild-type C57BL/6 mice (2 months of age) received 2 l of control (CHO medium), 7PA2 CM, or 7PA2 CM in combination with 17-AAG (100 M), via an implanted cannula.…”

“…PSD95 is the major scaffolding protein at excitatory synapses and in postsynaptic densities (PSDs) and is crucial for synapse maturation and plasticity (Sheng and Hoogenraad, 2007). The level of PSD95 protein is reduced in AD brains (Gylys et al, 2004), with the degree of reduction correlating with A␤ oligomer levels and the severity of dementia (Love et al, 2006;Proctor et al, 2010). A␤ oligomers have been reported to directly interact with PSD95 at postsynaptic sites (Pham et al, 2010) with the continuous overproduction of A␤ reducing the number and plasticity of local synapses (Wei et al, 2010).…”

“…Because most of Hsp90's "client proteins" are oncogenic or neurotoxic, it has long been postulated that Hsp90 inhibition exerts therapeutic effects by dissociating these toxic proteins and facilitating their degradation. Therefore, Hsp90 inhibitors were found to hold promise in treating neurodegenerative diseases, as they can clear inclusions, such as PolyQ, ␣-synuclein, and tau (Luo et al, 2010). In AD, Hsp90 inhibition has been extensively studied in regard to reducing tau pathology (Dickey et al, 2007).…”