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

ABSTRACT

INTRODUCTION: The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aß) 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 Aß plaque burden. METHODS: Mice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aß 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 Aß plaque burden was evaluated at each age after the completion of the behavioral tests. RESULTS: CRDN8 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 Aß 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. CONCLUSIONS: Our 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 Aß 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.