Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

Abstract

IntroductionThe current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aβ) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially the hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Aβ plaque burden.MethodsMice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests.ResultsCRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age.ConclusionsOur data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.

Elevated emotional contagion in a mouse model of Alzheimer’s disease is associated with increased synchronization in the insula and amygdala

“…Consistent with previous studies2238, the Tg mice exhibited gradual accumulation of amyloid plaques with disease progression. All LFP recording regions showed a significant correlation between amyloid burden and the OFC freezing level.…”

“…Although Tg-11 mice had lower freezing levels in the fear memory test, consistent with previous studies222324, indicating memory impairment, these mice showed considerably higher freezing levels in the OFC test compared to Wt-11 mice. Individual locomotor activity and freezing characteristics in fear conditioning did not affect the OFC freezing levels (Supplementary Fig.…”

IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior

“…As noted, IL-10 had minimal effect on learning and memory in the nTg littermates, but in the TgCRND8 transgenic mice, it significantly exacerbated context and tone fear memory, concurrent with marked loss of synaptic proteins. Although many studies suggest that soluble oligomeric species of Aβ are most often associated with various memory impairments in APP mice and humans (Zahs and Ashe, 2013), in TgCRND8 mice we have seen a strong correlation between total Aβ loads and impairments in fear conditioned memory (Hanna et al, 2012). Notably, multiple studies also show that increased insoluble APOE, both in humans and mice, is associated with worse cognitive function that is consistent with our observations (Bennett et al, 2005; Nilsson et al, 2004; Raber et al, 2000).…”

“…We assessed hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory in CRND8 mice (cohort A) (Figure 3A) (Hanna et al, 2012). All mice actively explored the novel environment of the training chamber and spent <3% of the total exploration time on pauses or immobility, with no significant differences between the groups (Figure 3B).…”

Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains

“…Conditioning was carried out in 4 identical chambers (25.3L Â 29.5W Â 29.5H cm; Coulbourn Instruments) as described (Hanna et al, 2012). The total floor area of each chamber was 746 cm 2 .…”