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.
Highlights
The current pathological confirmation of the diagnosis of Alzheimer’s disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Ab) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss
The results demonstrated that the Ab plaque burden significantly increased within the studied age range, and it was significantly associated with an overall impairment in contextual and tone fear memory in CRND8 mice
Ab plaque burden increases with age in CRND8 mice We previously demonstrated that amyloid plaque burden was significantly correlated with sodium dodecyl sulfate (SDS-) soluble and formic acid (FA-) extractable Ab fractions in the CRND8 model, and that both biochemical and histo-pathological analyses of Ab led to the same interpretations of cognitive impairment in multiple memory systems [24]
Summary
The current pathological confirmation of the diagnosis of Alzheimer’s disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Ab) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. Confirmation of a clinical diagnosis of AD still requires post mortem identification of parenchymal amyloid beta (Ab) deposits and intra-neuronal neurofibrillary tangles composed of abnormally phosphorylated tau protein [2,3,4,5] and severe loss of brain tissue [6,7,8]. Transgenic mice, over-expressing the mutated human amyloid precursor protein (APP) gene, provide a valuable tool for investigating the associations between amyloidosis, neuronal dysfunction, and cognitive impairment [19,20,21,22,23].
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